Activation of non-classical Wnt signaling pathway effectively enhances HLA-A presentation in acute myeloid leukemia.

Objective: The escape from T cell-mediated immune surveillance is an important cause of death for patients with acute myeloid leukemia (AML). This study aims to identify clonal heterogeneity in leukemia progenitor cells and explore molecular or signaling pathways associated with AML immune escape. Methods: Single-cell RNA sequencing (scRNA-seq) was performed to identified AML-related cellular subsets, and intercellular communication was analyzed to investigate molecular mechanisms associated with AML immune escape. Bulk RNA sequencing (RNA-seq) was performed to screen differentially expressed genes (DEGs) related to hematopoietic stem cell progenitors (HSC-Prog) in AML, and critical ore signaling pathways and hub genes were found by Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The mRNA level of the hub gene was verified using quantitative real-time PCR (qRT-PCR) and the protein level of human leukocyte antigen A (HLA-A) using enzyme-linked immuno sorbent assay (ELISA). Results: scRNA-seq analysis revealed a large heterogeneity of HSC-Prog across samples, and the intercellular communication analysis indicated a strong association between HSC-Prog and CD8+-T cells, and HSC-Prog also had an association with HLA-A. Transcriptome analysis identified 1748 DEGs, enrichment analysis results showed that non-classical wnt signaling pathway was associated with AML, and 4 pathway-related genes (RHOA, RYK, CSNK1D, NLK) were obtained. After qRT-PCR and ELISA validation, hub genes and HLA-A were found to be down-regulated in AML and up-regulated after activation of the non-classical Wnt signaling pathway. Conclusion: In this study, clonal heterogeneity of HSC-Prog cells in AML was identified, non-classical wnt signaling pathways associated with AML were identified, and it was verified that HLA-A could be upregulated by activation of non-classical wnt signaling, thereby increasing antigen presentation.

Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML.

Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07-0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

A comparison of WHO-5 and ICC classifications in a series of myeloid neoplasms, considerations for hematopathologists and molecular pathologists.

OBJECTIVES: The International Consensus Classification (ICC) and 5th Edition of the World Health Organization Classification (WHO-5) made substantive updates to the classification of myeloid neoplasms. This study compares the systems in a series of myeloid neoplasms with increased blasts, analyzing implications for diagnostic workflow and reporting. METHODS: Bone marrow biopsies categorized as myelodysplastic syndrome with excess blasts (MDS-EB) or acute myeloid leukemia (AML) by WHO-R4 were identified. Results of morphology review, karyotype, fluorescence in situ hybridization, and next-generation sequencing were compiled. Cases were retrospectively re-classified by WHO-5 and ICC. RESULTS: 46 cases were reviewed. 28 cases (61 %) had ≥20 % blasts, with the remaining cases having 5-19.5 % blasts. The most common differences in classification were 1) the designation of MDS versus MDS/AML (10/46, 22 %) for cases with 10-19 % blasts and 2) the ICC's designation of TP53 variants as a separate classifier for AML (8/46, 17 %). Bi-allelic/multi-hit TP53 alterations were identified in 15 cases (33 %). Variants of potential germline significance were identified in 29 (63 %) cases. CONCLUSIONS: While terminology differences between WHO-5 and ICC exist, both systems invoke similar opportunities for improved reporting: standardized classification of pathogenic variants (notably TP53), streamlined systems to evaluate for potential germline variants, and integrated reporting of morphologic and genetic data.

Guideline for treating relapsed or refractory myeloid leukemia in children with Down syndrome.

Treatment of relapsed and refractory myeloid leukemia in Down syndrome (r/r ML-DS) poses significant challenges, as prognosis is dire and there is no established standard treatment. This guideline provides treatment recommendations based on a literature review and collection of expert opinions, aiming to improve overall and event-free survival of patients. Treatment options include fludarabine and cytarabine (FLA) ± gemtuzumab ozogamicin (GO), azacytidine (AZA) ± panobinostat, and hematopoietic stem cell transplantation (HSCT). Preferred approaches are AZA ± panobinostat for cases with low blast count or FLA ± GO for cases with high blast count, followed by HSCT after remission. Further research is crucial for the investigation of targeted therapies (e.g., BH3 mimetics, LSD1, JAK inhibitors).

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Efficacy of venetoclax and rituximab in the treatment of concurrent acute myeloid leukemia and untreated chronic lymphocytic leukemia: A case report and literature review.

To date, few cases of concurrent acute myeloid leukemia (AML) and untreated chronic lymphocytic leukemia (CLL) have been reported. Due to the complexity of the pathogenesis and the absence of a uniform treatment regimen, the associated prognosis remains poor. The present study reports the case of a 58-year-old male with asymptomatic leukocytosis, who was previously healthy with no malignancies. Flow cytometry analysis revealed protocytosis, monocytosis and monoclonal B lymphocytosis in a bone marrow specimen. Results of a gene rearrangement assay demonstrated positive immunoglobulin heavy-chain variable region gene status in monoclonal B lymphocytes. Thus, the patient was diagnosed with AML with maturation (AML-M2) that co-existed with untreated CLL. The normative daunorubicin (40 mg/m2 on days 1-3) and cytarabine (80 mg/m2 on days 1-7) regimen combined with venetoclax (400 mg on days 1-7) and rituximab (375 mg/m2 on day 0) was used as induction chemotherapy. The patient achieved morphological complete remission in both AML and CLL following the first course of chemotherapy. In addition, the present study retrospectively analyzed the data of 22 patients with concurrent AML and untreated CLL, and the results demonstrated that the median age at the time of AML diagnosis was 69 years (range, 52-86 years). Moreover, the male:female ratio was 6.33:1 and AML-M2 was the most frequent subtype at diagnosis. The presence of a complex karyotype was associated with the poorest prognosis, and patients who received venetoclax often exhibited an improved prognosis. In conclusion, the combination of venetoclax and rituximab improves the prognosis of patients with concurrent AML and untreated CLL.

NAD metabolism-related genes provide prognostic value and potential therapeutic insights for acute myeloid leukemia.

Introduction: Acute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear. Methods: We utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature. Results: An 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target. Conclusion: Our study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.

Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately one third of acute myeloid leukemia (AML) patients. FLT3-Internal tandem duplication (FLT3-ITD) mutations are the most common FLT3 mutations and are associated with a poor prognosis. Gilteritinib is a FLT3 inhibitor that is US FDA approved for treating adult patients with relapsed/refractory AML and a FLT3 mutation. While gilteritinib monotherapy has improved patient outcome, few patients achieve durable responses. Combining gilteritinib with venetoclax (VEN) appears to make further improvements, though early results suggest that patients with prior exposure to VEN fair much worse than those without prior exposure. MRX-2843 is a promising inhibitor of FLT3 and MERTK. We recently demonstrated that MRX-2843 is equally potent as gilteritinib in FLT3-ITD AML cell lines in vitro and primary patient samples ex vivo. In this study, we investigated the combination of VEN and MRX-2843 against FLT3-ITD AML cells. We found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-mutated AML cell lines and primary patient samples. Importantly, we found that VEN synergistically enhances cell death induced by MRX-2843 in FLT3-ITD AML cells with acquired resistance to cytarabine (AraC) or VEN+AraC. VEN and MRX-2843 significantly reduce colony-forming capacity of FLT3-ITD primary AML cells. Mechanistic studies show that MRX-2843 decreases Mcl-1 and c-Myc protein levels via transcriptional regulation and combined MRX-2843 and VEN significantly decreases oxidative phosphorylation in FLT3-ITD AML cells. Our findings highlight a promising combination therapy against FLT3-ITD AML, supporting further in vitro and in vivo testing.

Acute myeloid leukemia with a novel AKAP9::PDGFRA fusion transformed from essential thrombocythemia: A case report and mini review.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark CALR mutation transforming to AML characterized by a previously unreported AKAP9::PDGFRA fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.

In Silico Drug Repurposing Against PSMB8 as a Potential Target for Acute Myeloid Leukemia Treatment.

PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the existing literature. The principal aim of this study is to systematically screen an expansive library of molecular entities, curated from various databases to identify the prospective inhibitory agents with an affinity for PSMB8. A comprehensive assortment of molecular compounds obtained from the ZINC15 database was subjected to molecular docking simulations with PSMB8 by using the AutoDock tool in PyRx (version 0.9.9) to elucidate binding affinities. Following the docking simulations, a select subset of molecules underwent further investigation through comprehensive ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis employing AdmetSar and SwissADME tools. Finally, RMSD, RMSF, Rg, and H bond analyses were conducted via GROMACS to determine the best conformationally dynamic molecule that represents the candidate agent for the study. Following rigorous evaluation, Adozelesin, Fiduxosin, and Rimegepant have been singled out based on considerations encompassing bioavailability scores, compliance with filter criteria, and acute oral toxicity levels. Additionally, ligand interaction analysis indicates that Adozelesin and Fiduxosin exhibit an augmented propensity for hydrogen bond formation, a factor recognized for its facilitative role in protein-ligand interactions. After final analyses, we report that Fiduxosin may offer a treatment possibility by reversing the low survival rates caused by PSMB8 high activation in AML. This study represents a strategic attempt to repurpose readily available pharmaceutical agents, potentially obviating the need for de novo drug development, and thereby offering promising avenues for therapeutic intervention in specific diseases.

Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2).

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.

Novel biomarkers to identify complicated course of febrile neutropenia in hematological patients receiving intensive chemotherapy.

Febrile neutropenia (FN) is a common consequence of intensive chemotherapy in hematological patients. More than 90% of the patients with acute myeloid leukemia (AML) develop FN, and 5%-10% of them die from subsequent sepsis. FN is very common also in autologous stem cell transplant recipients, but the risk of death is lower than in AML patients. In this review, we discuss biomarkers that have been evaluated for diagnostic and prognostic purposes in hematological patients with FN. In general, novel biomarkers have provided little benefit over traditional inflammatory biomarkers, such as C-reactive protein and procalcitonin. The utility of most biomarkers in hematological patients with FN has been evaluated in only a few small studies. Although some of them appear promising, much more data is needed before they can be implemented in the clinical evaluation of FN patients. Currently, close patient follow-up is key to detect complicated course of FN and the need for further interventions such as intensive care unit admission. Scoring systems such as q-SOFA (Quick Sequential Organ Failure Assessment) or NEWS (National Early Warning Sign) combined with traditional and/or novel biomarkers may provide added value in the clinical evaluation of FN patients.

Sorafenib maintenance in FLT3-ITD mutated AML after allogeneic HCT: a real-world, single-center experience.

Despite allogeneic hematopoietic stem cell transplant (allo-HCT) and the development of novel FLT3 inhibitors in both induction (midostaurin) and in the relapsed/refractory setting (gilteritinib), FLT3-ITD mutated leukemia (FLT3-ITD+ AML) still represents a challenge for modern hematology. Sorafenib is, to this date, the only inhibitor that demonstrated efficacy in improving both progression-free and overall survival as post-HCT maintenance therapy, even if its use in this setting has not been approved so far by regulatory agencies. The aim of our study was to evaluate the feasibility, safety, and efficacy of sorafenib maintenance in preventing early relapse in FLT3-ITD+ AML after HCT in a single-center experience. We analyzed 26 consecutive patients who received post-HCT 2-year maintenance with sorafenib at our center between 2017 and 2023. The median time from HCT to sorafenib start was 130 days, and the median dosage was 200 mg per day. Two (8%) and three (12%) patients discontinued maintenance due to toxicity and disease relapse, respectively. Eight (31%) patients terminated the 2-year maintenance and stopped sorafenib, while 13 patients are still under treatment. Overall, 21/26 patients (81%) are alive and in stable complete remission as outlined by a 2-year disease-free survival of 83.61%. No major long-term toxicity was reported at the last follow-up. Our real-world experience supports the use of sorafenib as a feasible and effective therapeutic option in post-HCT maintenance for FLT3-ITD+ AML.

Breakthrough Pneumocystis jirovecii Pneumonia in an Allogeneic Hematopoietic Stem Cell Transplant Recipient.

Pneumocystis carinii pneumonia (PCP), which is currently referred to as Pneumocystis jirovecii pneumonia, is an opportunistic fungal infection that commonly affects immunocompromised patients, and it is potentially fatal. Individuals at risk include those whose host immunity has been altered by underlying disease states, such as HIV and cancer patients, as well as transplant recipients and those taking immunosuppressive medications. Here, we present a case of a breakthrough PCP infection of an adult allogeneic hematopoietic stem cell transplant patient who was infected despite prophylaxis with inhaled pentamidine. The patient's transplant course was complicated by acute graft-versus-host disease (GVHD), which was treated with tacrolimus, prednisone, beclomethasone, and budesonide. Treatments for GVHD, which include immunosuppressive therapies, are a risk factor for PCP. Thus, the patient was on prophylactic treatment with inhaled pentamidine. The case presents challenges that immunocompromised patients face, particularly those undergoing allogeneic hematopoietic stem cell transplantation. While the patient received prophylactic treatment, there was still a breakthrough PCP infection. We highlight the risks this infection can cause and the need to promptly address these infections to prevent complications and optimize prophylactic regimens.

ITGAM sustains MAPK signaling and serves as an adverse prognostic factor and therapeutic target in acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is the second most frequently occurring type of leukemia in adults. Despite breakthroughs in genetics, the prognosis of AML patients remains dismal. The aim of this study is to find new therapeutic targets and diagnostic markers for AML and to explore their mechanisms of action. Methods: The expression patterns of integrin subunit alpha M (ITGAM) were investigated across different cell types using the Human Protein Atlas (HPA) database. The ITGAM levels across cancer types were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Prognostic correlations in AML individuals were evaluated using The Cancer Genome Atlas (TGCA) database. ITGAM-associated functions were evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The AML cells were transfected with short-hairpin RNA targeting ITGAM or a control, and subsequently subjected to analysis in order to ascertain the impact of ITGAM on proliferation and apoptosis. Results: The expression of ITGAM was significantly higher in the AML patient samples compared to the control samples. High ITGAM expression was significantly associated with poor overall survival (OS). The knockdown of ITGAM in the AML cells resulted in a decrease in proliferation and an increase in apoptosis. This was accompanied by cell cycle arrest at the G1 phase and a downregulation of protein production for cyclin D1, cyclin E1, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 4 (CDK4). A pathway analysis and a western blot analysis revealed that ITGAM positively regulated mitogen-activated protein kinase (MAPK) signaling by silencing attenuated p38 MAPK (P38), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) phosphorylation, while the total protein levels remained unchanged. Conclusions: ITGAM can serve as a potential prognostic biomarker and therapeutic target for AML. ITGAM production was elevated in AML and indicated poor survival. Silencing ITGAM suppressed AML cell viability and induced apoptosis by blocking cell cycle progression, likely by impeding the activation of the MAPK pathway. Further investigations that directly target the ITGAM-MAPK axis may offer novel strategies for mitigating AML pathogenesis and overcoming chemotherapy resistance.

Acute Leukemia and Latent Tuberculosis Infection in Italy: Quantiferon-Tb Test Screening in a Low Tuberculosis Incidence Country.

Background: Identification of latent tuberculosis infection (LTBI) is a critical step of tuberculosis surveillance, especially in low-incidence countries. However, it is limited to situations with a higher probability of developing active disease, e.g., patients with hematological malignancies. According to guidelines, in TB non-endemic countries, no clear screening program is established at diagnosis for patients with acute leukemia (AL). The primary endpoint of this study was to establish the prevalence of LTBI in patients with a diagnosis of AL using QuantiFERON (QFT)-TB. Secondarily, radiological and clinical features driving the increased risk of LTBI were evaluated. Methods: QFT-TB screening was performed before induction or consolidation in all patients with AL (myeloid and lymphoid) treated at our Institution between October 2019 and August 2023. Results: We accrued 62 patients, of whom 7 (11,3%) tested positive, without any symptoms or signs of active TB, and 2 (3,2%) resulted as indeterminate. All positive patients started prophylaxis with isoniazid 300 mg daily, while patients whose test was indeterminate did not receive any prophylaxis. Active TB was excluded by imaging, as well as microscopic, cultural, and molecular examination on bronchoalveolar lavage if signs of any infection were detected. During the 46 months of observation, no patients developed TB reactivation. Conclusions: Despite the low sample size, 1/10 of our patients had prior TB exposure, hinting that LTBI could be more common than expected in Italy. This finding suggests implementing TB screening in the pre-treatment setting, particularly at a time when more active treatments are becoming available also for patients ineligible for intensive chemotherapy.

Current landscape of CD3 bispecific antibodies in hematologic malignancies.

Over the past 30 years the incorporation of monoclonal antibody (mAb) treatments into the management of hematologic malignancies has led to significant improvements in patient outcomes. The key limitation of mAb treatments is the necessity for target antigen presentation on major histocompatibility complex (MHC) and costimulatory molecules to elicit a cytotoxic immune response. With the advent of bispecific antibodies (BsAbs), these limitations can be overcome through direct stimulation of cytotoxic T cells, thus limiting tumor cell evasion. BsAbs are rapidly being incorporated into treatment regimens for hematologic malignancies, and there are now seven FDA-approved treatments in this class, six of which have been approved in the past year. In this review we describe the function, complications, and clinical trial data available for CD3 BsAbs in the treatment of lymphoma, myeloma, and leukemia.

Tomatidine, a Steroidal Alkaloid, Synergizes with Cisplatin to Inhibit Cell Viability and Induce Cell Death Selectively on FLT3-ITD+ Acute Myeloid Leukemia Cells.

BACKGROUND: Acute Myeloid Leukemia (AML) is a hematological cancer that frequently presents with a range of side effects and drug resistance during anticancer drug treatment. The current study aims to achieve increased efficacy by combining lower doses of cisplatin with increasing concentrations of tomatidine in AML cells to increase efficacy. METHODS: Anti-proliferative effects of single and combination of cisplatin and tomatidine were assessed via MTT cell viability assay. The Annexin V/Propidium Iodide Double Staining method was used to measure the apoptotic effects of combined tomatidine and cisplatin treatment. Then, Western Blot analysis was performed to measure Poly (ADP-ribose) polymerase (PARP) and Caspase-3 protein expression levels. RESULTS: Cisplatin treatment with lower concentrations displayed high cytotoxic effects on AML cells, compared with tomatidine. The combination of the Inhibitory Concentration (IC) 20 value of cisplatin and increasing doses of tomatidine exhibited a significant decrease in cell viability relative to single treatments. The combination index analysis revealed a mild synergistic effect of cisplatin IC20 and varying tomatidine doses. The apoptosis induced when cisplatin was combined with 500 µM tomatidine by almost 20%, while the percentage of apoptosis in combination with 1 mM tomatidine was measured by 50% for both cell lines. The upregulation of proapoptotic cleaved-PARP (3.2 and 1.08-fold for THP-1 and MOLM-13, respectively) and downregulation in Caspase-3 (0.23 and 0.13-fold for THP-1 and MOLM-13, respectively) was detected. CONCLUSIONS: Together, the study indicated that when tomatidine combined with cisplatin on AML cell lines, a combinatorial anti-proliferative and apoptotic effect is observed. The combination of cisplatin with tomatidine may be a promising approach.