Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

New-onset aplastic anemia after SARS-CoV-2 vaccination.

Aplastic anemia (AA) is a rare autoimmune disease. Drugs, viruses, and radiation are among the most common etiologic factors, and most cases have immune pathophysiology. SARS-CoV-2 vaccines have been linked with rare side effects, including cases of acquired aplastic anemia. Here we review all the reported cases of new-onset AA after SARS-CoV-2 vaccination, and discuss their clinical characteristics and management. 18 patients in these case reports had a median age of 58 years. The time from vaccination to onset of aplastic anemia ranged from 1 day to 7 months, with a median of 2.5 weeks. Seventeen patients were diagnosed with severe or very severe aplastic anemia post-vaccination and all patients received standard treatments for acquired aplastic anemia. Seventeen patients achieved a complete or partial response and only 1 patient died. Aplastic anemia can be considered a very rare SARS-CoV-2 vaccine-related adverse event, although a causative relationship has not been proven. Reporting cases of such uncommon post-vaccination events could help clinicians to consider aplastic anemia when pancytopenia is observed after vaccination. The benefits of SARS-Cov-2 vaccination are established, and reports of rare events serve only to increase awareness in daily clinical practice.

A Panorama of Immune Fighters Armored with CARs in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating disease. Intensive chemotherapy is the mainstay of treatment but results in debilitating toxicities. Moreover, many treated patients will eventually require hematopoietic stem cell transplantation (HSCT) for disease control, which is the only potentially curative but challenging option. Ultimately, a subset of patients will relapse or have refractory disease, posing a huge challenge to further therapeutic decisions. Targeted immunotherapies hold promise for relapsed/refractory (r/r) malignancies by directing the immune system against cancer. Chimeric antigen receptors (CARs) are important components of targeted immunotherapy. Indeed, CAR-T cells have achieved unprecedented success against r/r CD19+ malignancies. However, CAR-T cells have only achieved modest outcomes in clinical studies on r/r AML. Natural killer (NK) cells have innate anti-AML functionality and can be engineered with CARs to improve their antitumor response. CAR-NKs are associated with lower toxicities than CAR-T cells; however, their clinical efficacy against AML has not been extensively investigated. In this review, we cite the results from clinical studies of CAR-T cells in AML and describe their limitations and safety concerns. Moreover, we depict the clinical and preclinical landscape of CAR used in alternative immune cell platforms with a specific focus on CAR-NKs, providing insight into the future optimization of AML.

Evidence that platelets from transfusion-dependent ß-thalassemia patients induce T cell activation.

A hypercoagulable state leading to increased risk for thrombotic events represents one of the most common complications observed in transfusion-dependent ß-thalassemia (TDT) patients. TDT patients have increased frequencies of circulating activated platelets. However, there is no information so far if platelets from TDT patients can activate T cells. In the present study we showed that T cells treated with platelets from TDT patients showed significant increased surface expression of CD69 compared to the T cells treated with platelets from healthy individuals. Patients with splenectomy showed increased T cell activation compared to patients with intact spleen. No T cell activation was observed following incubation with plasma alone, nor with platelets from healthy subjects. The percentages of regulatory T cells (Tregs) were also examined. TDT patients showed statistically significant increased percentages of Tregs compared to healthy controls. Additionally, we observed a positive statistically significant correlation between the percentages of Tregs and the platelet-induced activated T cells in patients who were not treated with aspirin. TDT patients showed increased levels of sP-selectin, suPAR and GDF-15, molecules implicated in platelet activation. We show that platelets from TDT patients can activate T cells in vitro. This activation correlates with markers of platelet activation and increased numbers of Tregs, perhaps in an effort to eliminate immune dysregulation, conceivably secondary to platelet activation.

Telomere biology: from disorders to hematological diseases.

Variations in the length of telomeres and pathogenic variants involved in telomere length maintenance have been correlated with several human diseases. Recent breakthroughs in telomere biology knowledge have contributed to the identification of illnesses named "telomeropathies" and revealed an association between telomere length and disease outcome. This review emphasizes the biology and physiology aspects of telomeres and describes prototype diseases in which telomeres are implicated in their pathophysiology. We also provide information on the role of telomeres in hematological diseases ranging from bone marrow failure syndromes to acute and chronic leukemias.

Immune response and adverse events after vaccination against SARS-CoV-2 in adult patients with transfusion-dependent thalassaemia.

Patients with transfusion-dependent thalassaemia (TDT) are considered an at increased-risk population for severe and/or morbid coronavirus disease 2019 (COVID-19) infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions after vaccination have been reported, with severe ones being extremely rare. Patients with TDT may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. Here, we show that adult patients with TDT following vaccination with the novel messenger RNA vaccines have mild adverse events and can produce protective antibodies comparable to the healthy population.

Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities.

BACKGROUND: The prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. Natural Killer (NK) cells can elicit an antileukemic response via a repertoire of activating receptors that bind AML surface ligands. NK-cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity and interleukin (IL)-15 to enhance their persistence. METHODS: We characterized in detail NK-cell populations expressing a panel of AML (CD123)-specific CARs and/or IL-15 in vitro and in AML xenograft models. RESULTS: CARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ Chimeric Antigen Receptor (CAR)-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK-cell persistence. Transgenic expression of secretory interleukin (sIL)-15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK-cell subsets. 2B4.ζ/sIL-15 CAR and sIL-15 NK cells maintained an overall activated NK-cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK-cell groups. In vivo, 2B4.ζ/sIL-15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL-15 CAR and sIL-15 NK cells induced lethal toxicity in a second model. CONCLUSION: Transgenic expression of CD123-CARs and sIL-15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early-phase clinical testing.

How to Make the Right Diagnosis in Neutropenia.

Isolated neutropenia without anemia or thrombocytopenia is a common clinical problem. The etiology of neutropenia may vary from transient bone marrow suppression, caused by self-limited viral illnesses, to previously undiagnosed congenital syndromes or serious systemic diseases. Consequently, determining the underlying cause of neutropenia and what treatment is required can be challenging. Acquired neutropenia is common and most of the times an etiologic factor can be found. Congenital neutropenia (CN) is rare, and we still have a lot to learn from mutational analysis as to the exact role of gene abnormalities in the pathogenesis of these complex diseases. This mini-review discusses a proposed approach to neutropenia in the adult patient.

Red Blood Cell Distribution Width: Another Prognostic Factor for COVID-19?

The coronavirus disease 2019 (COVID-19) is a pandemic with a high rate of hospitalization, admission to intensive care units, and mortality. Identifying patients at the highest risk for severe disease is important to facilitate early, aggressive intervention. High red blood cell distribution width (RDW) values are associated with increased mortality in the general population in patients suffering from several conditions, including cardiovascular disease, sepsis, acute kidney injury, chronic obstructive pulmonary disease, and hepatitis B. Our study aimed to determine whether RDW levels in all COVID-19 confirmed cases admitted to the Patras University Hospital, Greece, was an independent prognostic factor of hospitalization and disease outcome.

Immune Checkpoint Inhibitor-Associated Scleroderma-Like Syndrome: A Report of a Pembrolizumab-Induced "Eosinophilic Fasciitis-Like" Case and a Review of the Literature.

Immune checkpoint inhibitors are a promising new therapeutic strategy in oncology that aims to eliminate cancer cells by enhancing patients' immune response against tumor antigens. Despite their beneficial effects, immune checkpoint inhibitors are also responsible for a plethora of autoimmune manifestations, known as immune-related adverse events. We present a case of eosinophilic fasciitis-like disorder in an 81-year-old patient treated with the programmed death cell protein 1 inhibitor pembrolizumab for non-small-cell lung cancer. The patient developed characteristic indurated skin lesions in his limbs after 1½ years of treatment with pembrolizumab and a typical "groove sign." Raynaud's syndrome was absent. A full-thickness biopsy confirmed the clinical diagnosis of an "EF-like" condition. Neither peripheral eosinophilia nor eosinophilic infiltrates in the skin biopsy were found. His symptoms improved after a 2.5-month CPI discontinuation and treatment with 16 mg of methylprednisolone slowly tapered to a dose of 4 mg. Eosinophilic fasciitis is a rare immune-related adverse event of CPI treatment; our literature search identified only 12 cases that fulfill the criteria of EF in patients receiving CPIs.

Hepatocellular Carcinoma: An Uncommon Metastasis in the Orbit.

Hepatocellular carcinoma (HCC) represents the most common type of primary cancer of the liver and is associated with poor prognosis. It is the most common cause of death in cirrhotic patients and in different studies was shown as the third most common cause of cancer-related deaths worldwide. Each year, approximately half a million people are diagnosed with HCC. In recent decades, the prognosis of patients with HCC has improved because more cases are diagnosed and treated at early stages; high-risk patients (i.e., with chronic HBV or HCV infection) are followed more often for the possibility of HCC, and novel treatment options such as locoregional therapy are used with better overall results. The extrahepatic metastases represent a poor prognostic factor. The most common sites of metastasis in advanced hepatocellular carcinoma are the lung (44%), portal vein (35%), and portal lymph nodes (27%). Also, intra-abdominal lymph nodes and bones are common sites. Orbital metastases rarely occur, representing the 3-7% of orbital masses. These metastases are usually found in advanced tumor stages. The mechanism of metastasis to the orbit is difficult to determine. A hematogenous route, as for other primary neoplasms of the abdomen, may be suspected. Tumor cells may circulate through the vena cava, beyond the pulmonary filter to the heart, and finally be distributed to the orbital region through the arterial systemic circulation. We describe herein a case of an adult male with liver cirrhosis due to alcohol abuse who presented with concomitant diagnosis of HCC and orbit metastasis.

Idiopathic Aplastic Anemia: An Update.

"Bone marrow failure" encompass all the conditions and syndromes in which there are qualitative or quantitative disorders of one or more lineages (erythroid, myelomonocytic, and/or megakaryocytic). A few years ago, the pathophysiology of these syndromes was completely unknown. Today we have better knowledge for these diseases, allowing the development of new treatment options and the improvement of patients' outcome. Acquired bone marrow failure syndromes include myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria, idiopathic neutropenia and large granular leukemia. All these syndromes share some common features and pathophysiology. The most important feature is the possibility of clonal evolution and progression into acute myelogenous leukemia, and open questions still remain on how to prevent evolution in these patients.

Th1/17 cells, a subset of Th17 cells, are expanded in patients with active systemic lupus erythematosus.

Skewed cytokine production characterizes T cells in Systemic Lupus Erythematosus (SLE). Among Th17 cells that are expanded in lupus, a subset (Th1/17) retains the ability to produce IFNγ. We aimed to analyze Th17 and Th1/17 cells in patients with SLE. Patients with active disease displayed increased percentages of circulating Τh17 and Th1/17 cells. Stimulated T cells from patients with lupus secreted significantly more IL-17 compared to healthy donors. Also, T cells from patients with active SLE released significantly lower levels of IFN-γ compared to controls. However, following stimulation, levels of IFN-γ also rose significantly. Our data suggest that lupus Th1/17 cells are not only expanded but also functional. In summary, in this study it was shown that patients with active SLE display increased Th17 and functional Th1/17 cells. This impaired T-cell axis might represent a possible future therapeutic target.

The role of platelets in autoimmunity, vasculopathy, and fibrosis: Implications for systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, autoimmunity, and widespread dermal and visceral fibrosis. This article summarizes the current knowledge about the potential contribution of platelets in the disease process and the rationale of targeting platelets as an adjunct treatment for SSc. METHODS: We performed an electronic search (Medline) using the keywords platelets, systemic sclerosis, autoimmunity, fibrosis, Raynaud, and pulmonary arterial hypertension. RESULTS: The link that connects vasculopathy, autoimmunity, and fibrosis in SSc remains obscure. Experimental data suggest that platelets are not solely cell fragments regulating hemostasis but they have a pleiotropic role in several biologic processes including immune regulation, vasculopathy, fibrosis, and all key features of SSc. Platelets interplay with the impaired endothelium, can interact with immune cells, and they are storages of bioactive molecules involved in tissue injury and remodeling. The potential role of platelets in the pathogenesis of SSc is further supported by experimental data in animal models of SSc. Platelet-derived serotonin represents a novel target in SSc and serotonin blockade is currently being tested in clinical trials. CONCLUSION: Platelets may be actively involved in the pathogenesis of SSc by activating immune responses and facilitating the fibrotic process. However, definite conclusions cannot be drawn until more data from both basic and clinical research are available.

Alterations in T-lymphocyte subpopulations in patients with complicated liver cirrhosis.

AIM: To investigate possible alterations of T-lymphocyte subpopulations in patients with cirrhosis complicated with infection and variceal bleeding, and to evaluate the relationship between T-lymphocyte subpopulations and outcome. PATIENTS AND METHODS: This was a prospective study on 99 patients with liver cirrhosis, who were admitted to a university hospital over a period of 18 months. Twenty-six patients (37.6%, group A) were admitted for reasons other than infection or bleeding, 24 (34.7%, group B) presented with sepsis, and 19 (27.5%, group C) were admitted with variceal bleeding. A group of 30 healthy individuals admitted to the hospital without cirrhosis and served as the control group. We evaluated T-cell subsets CD3, CD4, CD5, CD8, CD56, and CD20 as well as CD14 and CD64 subsets of monocytes and neutrophils by using flow cytometry. Measurements for group A were taken only on admission, while for patients of group B and C measurements were repeated on the third and the last hospital day. RESULTS: T-cell subsets (CD3, CD4, CD5, CD8, CD56, and CD20 as well as CD14 and CD64 subsets of monocytes and neutrophils) were reduced in septic cirrhotics, but this reduction was not statistically significant compared to the other groups. A significant decrease was observed in T helper cells between cirrhotic patients with and without variceal bleeding (day 3: CD4: 293 ± 214 versus 442 ± 277 [P < 0.049]; discharge day: CD4:178 ± 113 versus 442 ± 277 [P < 0.003]). Concerning phagocytic potential as detected by CD14 and/or CD64 expression on monocytes and neutrophils, a significant decrease was noted in septic versus nonseptic cirrhotics (day 1: 61.66 ± 40.16 versus 252 ± 73 [P < 0.039]; day 3: 66.99 ± 34.64 versus 252 ± 73 [P < 0.042]). CONCLUSIONS: Our study showed that the T helper cells and phagocytic potential of monocytes and neutrophils are decreased in patients with liver cirrhosis complicated by sepsis and variceal bleeding. Particularly, these abnormalities seem to be more pronounced in cirrhosis with variceal bleeding. To our knowledge, this is the first study to show these T-cell abnormalities in patients with cirrhosis. Further studies are needed to confirm these findings.

Malaria: a haematological disease.

Plasmodium falciparum malaria remains a major cause of mortality throughout the tropical world. Haematological abnormalities are considered a hallmark of malaria, bearing an impact on final outcome and representing indices of prognostic and follow-up value. These include severe anaemia, coagulation disturbances, leukocyte numerical or functional changes and spleen involvement. Anaemia involves red blood cell lysis due to parasite invasion, as well as mechanisms of intravascular haemolysis and decreased erythropoiesis. Exchange or blood transfusion is mainly recommended in the management of these patients. Haemorrhagic complications in severe malaria are relatively rare despite prominent thrombocytopenia and dysfunction in the coagulation pathway. Numerical, as well as functional changes in the white blood cell are less dramatic than other blood cell series, but still, remain a significant index of disease progression and ultimate prognosis. Finally, the role of the spleen in severe malaria is multifactorial. Care and vigilance should be taken against splenic rupture which is fatal and can occur despite appropriate antimalarial prophylaxis and treatment.