Seminars in hematology最新文献

Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape of blood cancers. These engineered receptors which endow T cells with antibody-like target cell recognition combined with the typical T cell target cell lysis abilities. Introduced into the clinic in the 2010s, CAR T-cells have shown efficacy in chronic B lymphocytic leukemia (CLL), but a majority of patients do not achieve sustained remission. Here we discuss the current treatment landscape in CLL using small molecules and allogeneic stem cell transplantation, the niche CAR T-cells filled in this context, and what we have learned from biomarker and mechanistic studies. Several product parameters and improvements are introduced as examples of how the bedside-to-bench is translated into improved CAR T-cells for CLL. We hope to convey to our readers the crucial role translational medicine plays in transforming the treatment outcomes for patients with CLL and how this line of research is an essential component of modern medicine.

Patients with hematologic conditions have a higher risk of severe COVID-19 and COVID-19-related death. This is related to immune deficiencies induced by hematologic conditions and/or the treatment thereof. Prospective vaccine immunogenicity studies have demonstrated that in the majority of patients, a 3-dose COVID-19 vaccination schedule leads to antibody concentrations comparable to levels obtained in healthy adults after a 2-dose schedule. In B cell depleted patients, humoral responses are poor, however vaccination did induce potent cellular immune responses. The effect of 3-dose vaccination schedules and COVID-19 booster vaccinations on the protection of patients with hematologic malignancies against severe COVID-19 and COVID-19 related death remains to be confirmed by population-based vaccine effectiveness studies.

Natural killer (NK)/T-cell lymphomas arise mainly from NK-cells and occasionally T-cells, and are universally infected with Epstein Barr virus (EBV). They are uncommon lymphomas more prevalent in Asian and Central/South American populations. NK/T-cell lymphomas are clinically aggressive and predominantly extranodal. The most commonly involved sites are the nasal cavity, followed by non-nasal sites including the skin, gastrointestinal tract and testis. The diagnosis of extranodal NK/T-cell lymphoma is established with histological and immunohistochemical examination, together with the demonstration of EBV in the tumour cells. Staging by positron emission tomography computed tomography is essential to inform the optimal management. Plasma EBV DNA quantification should be performed as it serves as a marker for prognostication and treatment response. Survival outcomes of patients with early-stage disease are good following treatment with nonanthracycline based chemotherapy, together with sequential/concurrent radiotherapy. For advanced-stage disease, asparaginase-containing regimens are mostly used and allogeneic haematopoietic stem cell transplantation should be considered for those at high risk of relapse. Salvage chemotherapy is largely ineffective for relapsed/refractory disease, which has a grave prognosis. Novel therapeutic approaches including immune check-point blockade, EBV-specific cytotoxic T-cells, and monoclonal antibodies are being investigated to improve outcomes for those with high risk and relapsed/refractory disease.

Hepatitis C virus (HCV) is a hepatotropic and lymphotropic virus, responsible for both chronic hepatitis and extra-hepatic manifestations. Multiple epidemiologic, clinical, biological, and molecular studies have suggested that HCV plays a causal role also in the development of several lymphoproliferative disorders, either benign, such as mixed cryoglobulinemia, or malignant, such as B-cell non-Hodgkin lymphomas (NHL). Chronic viral antigenic stimulation of B-lymphocytes plays a fundamental basic role from the onset of lymphoma to its final steps. In the past, several studies demonstrated that the association of pegylated interferon plus ribavirin was able to eradicate HCV, with subsequent regression of indolent B-cell low-grade NHL. Other studies have demonstrated that direct antiviral agents (DAAs) therapy have some efficacy in HCV-associated NHL, particularly in patients with low-grade NHL or marginal zone-lymphoma, but these results need to be confirmed in larger studies with longer follow-up. The response rate of antiviral therapy seems favorable also in high grade NHL when DAAs therapy is administered in combination with chemotherapy and therefore antiviral therapy should be considered as a first-line approach in HCV-related NHL.

Lymphomas are among the most common cancers in people with HIV (PWH). The lymphoma subtypes and pathogenesis of lymphoma in PWH are different from the immunocompetent population. It is well-known that HIV causes severe CD4⁺ T cell lymphopenia in the absence of antiretroviral therapy (ART); however, the risk of developing certain subtypes of lymphoma remains elevated even in people receiving ART with preserved CD4⁺ T cells. HIV contributes to lymphomagenesis and causes decreased immune surveillance via T cell depletion and dysregulation, B cell dysregulation, and the potential contribution of HIV-encoded proteins. The oncogenic gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV, also known as human herpesvirus 8), are the causative agents in the majority of HIV-associated lymphomas. HIV-associated T cell depletion and dysregulation allows EBV and KSHV to proliferate in infected B cells. Specific EBV- and KSHV-encoded proteins participate in B cell activation, and proliferation leading to B cell transformation. Understanding the distinct pathogenesis of HIV-associated lymphomas affords opportunities to develop therapies that specifically target these unique aspects and improve lymphoma outcomes in PWH. Agents being studied that target the specific roles of HIV, EBV, and KSHV in lymphomagenesis include immunotherapies, targeted agents, and cellular therapies.

Large scale high-throughput DNA sequencing studies have identified clonal hematopoiesis (CH) as a clinical phenomenon characterized by a disproportionately large clonal population in the hematopoietic system with a shared mutational background. CH originates through mutations in hematopoietic stem and progenitor cells (HSPCs) which provide a proliferative advantage over unmutated HSPCs and has been characterized as a risk factor for myeloid neoplasm (MN) development. Large population studies found that CH is an age-related event which is commonly found in association with milder phenotypes such as cytopenia, mild monocytosis, intravascular hemolysis, or chronic inflammation. More importantly, the vast majority of individuals with CH are asymptomatic and healthy people of advanced age, where the impact of CH is thus considered to be of indeterminate potential (CHIP). These conditions are sometimes referred to as benign to facilitate distinction from overt MN but, despite this definition, may still result in severe illness, reduced overall survival, and increased risk of hematologic neoplasms development and all-cause mortality. The purpose of this review is to describe clinical conditions associated with CH, the clinical significance of CH-related clinical phenotypes, and the determinants of progression from CH to overt MN following the paradigmatic example of SF3B1-driven CH.

Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by insufficient blood cell production and increased risk of transformation to myeloid malignancies. While genetically diverse, IBMFS are collectively defined by a cell-intrinsic hematopoietic stem cell (HSC) fitness defect that impairs HSC self-renewal and hematopoietic differentiation. In IBMFS, HSCs frequently acquire mutations that improve cell fitness, a phenomenon known as somatic compensation. Somatic compensation can occur via distinct genetic processes such as loss of the germline mutation or somatic alterations in pathways affected by the disease-causing gene. While the clinical implications of somatic compensation in IBMFS remain to be fully discovered, understanding these mutational processes can help understand disease pathophysiology and may inform future diagnostic and therapeutic approaches. In this review, we highlight current understanding about somatic compensation in IBMFS.