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Myelodysplastic syndrome and acute myeloid leukemia (AML) belong to a continuous disease spectrum of myeloid malignancies with poor prognosis in the relapsed/refractory setting necessitating novel therapies. Natural killer (NK) cells from patients with myeloid malignancies display global dysfunction with impaired killing capacity, altered metabolism, and an exhausted phenotype at the single-cell transcriptomic and proteomic levels. In this study, we identified that this dysfunction was mediated through a cross-talk between NK cells and myeloid blasts necessitating cell-cell contact. NK cell dysfunction could be prevented by targeting the αvβ-integrin/TGF-β/SMAD pathway but, once established, was persistent because of profound epigenetic reprogramming. We identified BATF as a core transcription factor and the main mediator of this NK cell dysfunction in AML. Mechanistically, we found that BATF was directly regulated and induced by SMAD2/3 and, in turn, bound to key genes related to NK cell exhaustion, such as HAVCR2, LAG3, TIGIT, and CTLA4. BATF deletion enhanced NK cell function against AML in vitro and in vivo. Collectively, our findings reveal a previously unidentified mechanism of NK immune evasion in AML manifested by epigenetic rewiring and inactivation of NK cells by myeloid blasts. This work highlights the importance of using healthy allogeneic NK cells as an adoptive cell therapy to treat patients with myeloid malignancies combined with strategies aimed at preventing the dysfunction by targeting the TGF-β pathway or BATF. Editor's summary: Patients with myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), often relapse after standard of care. To improve outcomes, Kumar et al. have investigated the role of natural killer (NK) cells in antitumor immunity against myeloid blasts and have identified global dysfunction of NK cells in these patients. They identified BATF as responsible for this dysfunction, and by knocking out BATF downstream of the TGF-β canonical pathway in NK cells, they were able to enhance NK cell function against AML in vitro and in vivo. This has led to the initiation of a promising clinical trial using these TGFBR2 knockout NK cells against myeloid malignancies. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

Bispecific antibodies have shown significant clinical efficacy in patients with relapsed/refractory B‐cell non‐Hodgkin lymphomas and multiple myeloma, expanding treatment options for these patients. While these advancements are promising, it is important to be aware of associated side effects, such as cytokine release syndrome, neutropenia and infections. Gonugunta et al. provide valuable insights into the infection risks linked to the use of bispecific antibodies in haematological malignancies, drawing on both clinical trial data and real‐world experiences. Commentary on: Gonugunta et al. Risk of infections with bispecific antibodies in B‐cell non‐Hodgkin lymphomas and multiple myeloma—The current state. Br J Haematol 2024; 205:1197‐1201. [ABSTRACT FROM AUTHOR]

Summary: Adoptive cellular therapy using chimeric antigen receptor (CAR) T cells has led to a paradigm shift in the treatment of various hematologic malignancies. However, the broad application of this approach for myeloid malignancies and solid cancers has been limited by the paucity and heterogeneity of target antigen expression, and lack of bona fide tumor‐specific antigens that can be targeted without cross‐reactivity against normal tissues. This may lead to unwanted on‐target off‐tumor toxicities that could undermine the desired antitumor effect. Recent advances in synthetic biology and genetic engineering have enabled reprogramming of immune effector cells to enhance their selectivity toward tumors, thus mitigating on‐target off‐tumor adverse effects. In this review, we outline the current strategies being explored to improve CAR selectivity toward tumor cells with a focus on natural killer (NK) cells, and the progress made in translating these strategies to the clinic. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time‐to‐treatment for autologous CAR‐T cells, and the risk of graft‐versus‐host disease (GvHD) associated with allogeneic CAR‐T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR‐based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK‐cell therapy, and the strategies to overcome the challenges encountered. [ABSTRACT FROM AUTHOR]

Summary: The past decade has witnessed tremendous progress in the treatment of acute lymphoblastic leukaemia (ALL), primarily due to the development of targeted therapies, including tyrosine kinase inhibitors targeting BCR‐ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20 and CD22), bispecific antibodies and chimeric antigen receptor T‐ cell therapy. A number of new therapies have been approved by the US Food and Drug Administration in the past 5 years, including blinatumomab in 2014, inotuzumab ozagamicin in 2017 and tisagenlecleucel in 2017 for relapsed/refractory ALL. This has led to tremendous improvement in long‐term survival, of more than 50% in patients with precursor B‐ALL [50–70% in patients with Philadelphia chromosome (Ph)‐positive ALL)], 50–60% in T‐ALL and 80% in mature B‐ALL. Research is ongoing to optimize the benefit of targeted therapeutics with the goal of decreasing the use of cytotoxic therapies. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with a bimodal distribution. The progresses made in understanding its biology led to the development of targeted therapies. In this review, we summarize the current and future approaches in management of adult ALL. Tyrosine kinase inhibitors (TKI) targeting BCR-ABL1 tyrosine kinase, monoclonal antibodies targeting cell surface antigens (CD19, CD20, and CD22), bispecific antibodies, and chimeric antigen receptor (CAR)-T therapy are breakthrough treatments. They resulted in FDA approvals of blinatumomab in 2014, inotuzumab ozagamicin in 2017, and tisagenlecleucel in 2017 for relapsed/refractory ALL. Currently, long-term survival is achieved in more than 50% of patients with precursor B-ALL (50–70% in patients with Philadelphia chromosome (Ph)-positive ALL), 50–60% T-ALL, and 80% mature B-ALL. Ongoing efforts exist to optimize therapeutic options in both the relapsed/refractory as well as the frontline settings. In the era of precision medicine, the future lies in using less cytotoxic and more targeted agents. [ABSTRACT FROM AUTHOR]

Background: Our objective was to determine the effect of post‐diagnosis aspirin use on survival in veterans with head and neck squamous cell carcinoma. Methods: Retrospective cohort study of 584 veterans with head and neck squamous cell carcinoma treated at the Washington DC VA Medical Center between 1995 and 2015. Charts were queried for clinical‐pathologic data, aspirin prescriptions, and outcome. The Kaplan–Meier method was used to determine overall survival (OS) and disease‐specific survival (DSS) among aspirin users and nonusers. Results: A total of 329 patients met inclusion criteria. Primary subsites included oropharynx (n = 143), larynx (n = 105), oral cavity (n = 62), and hypopharynx (n = 19). Eighty‐four patients were aspirin users (25.5%). Aspirin users demonstrated significantly better 3‐year OS and DSS (78.6% and 88.1%) compared to nonaspirin users (OS: 55.9% and DSS: 70.2%; P = .0003 and P = .0019, respectively). On multivariate analysis, aspirin use remained independently associated with improved survival. Conclusion: Aspirin use following diagnosis and curative treatment of head and neck squamous cell carcinoma is associated with improved OS and DSS. [ABSTRACT FROM AUTHOR]

Although significant advances have been made in the biologic understanding of graft-versus-host disease (GVHD) and its treatment options, GVHD remains the single most challenging obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) due to high risk of disabling morbidity and mortality. Extracorporeal photopheresis (ECP) has promising effects in controlling steroid-refractory GVHD, both acute and chronic, and it has been studied extensively. Its putative immunomodulatory mechanisms, while not immunosuppressive, position ECP as an attractive treatment strategy for GVHD patients who are already receiving global immunosuppression. However, ECP is relatively underutilized due in part to limited access and time commitment. Here, we review the recent findings on the ECP efficacy in both acute and chronic GVHD, primarily for steroid-refractory status, and we critically appraise its benefits. We also explore salient considerations on the optimal use of ECP in the treatment of refractory GVHD. [ABSTRACT FROM AUTHOR]

Clinical Practice Points. Plasmablastic lymphoma (PBL) is a rare and highly aggressive variant of diffuse large B cell lymphoma with median survival of advanced stage patients varying between 6 and 15 months in previous reports. We report here a human immunodeficiency virus-infected patient surviving over 12 years following treatment for advanced PBL with EPOCH chemotherapy and intrathecal therapy. This case highlights the potential for improved survival in PBL with intensive chemotherapy. Further, literature review suggests promising prospects utilizing novel targeted therapies to increase the rate of prolonged responses. [ABSTRACT FROM AUTHOR]

Background Anthracycline adjuvant therapy has taken a particular role in the treatment of early stage breast cancer with an associated decrease in rates of both relapse and death. Their success however has been limited by their myelosuppression and their well-established risk of cardiac dysfunction. Guidelines have emerged that would limit the maximum lifetime dose of anthracyclines and make a baseline assessment and periodic monitoring of cardiac function part of the routine practice, which could be cumbersome, and may condemn the patient to an unwarranted modification of his/her regimen. Our study aimed at assessing the incidence of abnormal baseline echocardiography in asymptomatic women with breast cancer prior to anthracycline therapy and establishing risk criteria associated with abnormal echocardiograms at baseline. Methods 220 Patients seen at AUBMC (American University of Beirut Medical Center) who had non- metastatic breast cancer, and had an echocardiography performed before starting anthracycline chemotherapy were chosen. Data about demographic characteristics, tumor characteristics, baseline echocardiography results, and change in clinical decision was collected. Patients with suboptimal (less than 50%) ejection fraction (EF) on baseline echocardiography were analyzed for the prevalence of cardiac risk factors. Results were compared to those among the overall study group using Fisher's Exact test. A p- value of = < 0.05 was used as reference for statistical significance. Results All 220 of our patients had received a baseline echo prior to initiation of anthracycline therapy. 6.7% of these patients had already some abnormality in wall motion but only 2.7% had a suboptimal ejection fraction. 1.3% had a change in chemotherapy regimen based on ejection fraction. The patients with depressed EF had higher rates of CAD (coronary artery disease), diabetes, hypertension and dyslipidemia than the overall study group but without statistical significance. Conclusions Our study, as well as the previous contingent studies raise the question about routine echocardiography prior to anthracycline therapy and might eventually lead to a modification of current practice guidelines. [ABSTRACT FROM AUTHOR]