Seminars in hematology最新文献

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by profound alterations and defects in the T-cell compartment. This observation has gained renewed interest as T-cell treatment strategies, which are successfully applied in more aggressive B-cell malignancies, have yielded disappointing results in CLL. Despite ongoing efforts to understand and address the observed T-cell defects, the exact mechanisms and nature underlying this dysfunction remain largely unknown. In this review, we examine the supporting signals from T cells to CLL cells in the lymph node niche, summarize key findings on T-cell functional defects, delve into potential underlying causes, and explore novel strategies for reversing these deficiencies. Our goal is to identify strategies aimed at resolving CLL-induced T-cell dysfunction which, in the future, will enhance the efficacy of autologous T-cell-based therapies for CLL patients.

Chronic lymphocytic leukemia (CLL) cells circulate between peripheral (PB) blood and lymph node (LN) compartments, and strictly depend on microenvironmental factors for proliferation, survival and drug resistance. All cancer cells display metabolic reprogramming and CLL is no exception – though the inert status of the PB CLL cells has hampered detailed insight into these processes. We summarize previous work on reactive oxygen species (ROS), oxidative stress, and hypoxia, as well as the important roles of Myc, and PI3K/Akt/mTor pathways. In vitro co-culture systems and gene expression analyses have provided a partial picture of CLL LN metabolism. New broad omics techniques allow to obtain molecular and also single-cell level understanding of CLL plasticity and metabolic reprogramming. We summarize recent developments and describe the new concept of glutamine addiction for CLL, which may hold therapeutic promise.

Sequence convergence, otherwise stereotypy, of B-cell receptor immunoglobulin (BcR IG) from unrelated patients is a distinctive feature of the IG gene repertoire in chronic lymphocytic leukemia (CLL) whereby patients expressing a particular BcR IG archetype are classified into groups termed stereotyped subsets. From a biological perspective, the fact that a considerable fraction (∼41%) of patients with CLL express (quasi)identical or stereotyped BcR IG underscores the key role of antigen selection in the natural history of CLL. From a clinical perspective, at odds with the pronounced heterogeneity of CLL at large, patients belonging to the same stereotyped subset display consistent clinical presentation and outcome, including response to treatment, likely as a reflection of consistent biological background. Many major stereotyped subsets were recently shown to have satellites, that is, smaller subsets that are immunogenetically similar. Preliminary evidence supports that this similarity extends to shared biological and even clinical features, with important implications for patient stratification. Consequently, BcR IG stereotypy emerges as a powerful tool for dissecting the heterogeneity of CLL toward refined risk stratification and, eventually, more precise therapeutic interventions.

Aberrant signal transduction through the B cell receptor (BCR) plays a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). BCR-dependent signaling is necessary for the growth and survival of neoplastic cells, making inhibition of down-stream pathways a logical therapeutic strategy. Indeed, selective inhibitors against Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) have been shown to induce high rates of response in CLL and other B cell lymphomas. In particular, the development of BTK inhibitors revolutionized the treatment approach to CLL, demonstrating long-term efficacy. While BTK inhibitors are widely used for multiple lines of treatment, PI3K inhibitors are much less commonly utilized, mainly due to toxicities. CLL remains an incurable disease and effective treatment options after relapse or development of TKI resistance are greatly needed. This review provides an overview of BCR signaling, a summary of the current therapeutic landscape, and a discussion of the ongoing trials targeting BCR-associated kinases.

Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and cellular immune response to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response in patients with CLL.

Therapeutic targeting of apoptosis with small molecule B-cell lymphoma 2 (BCL-2) inhibition with venetoclax is highly efficacious in CLL, leading to sustained deep responses, particularly among patients with treatment-naïve disease with favorable prognostic markers. Patients with unfavorable genetic characteristics such as TP53 aberration and unmutated IGHV may also derive durable benefits, but their remission duration after time-limited venetoclax-containing combination therapy is shorter, particularly in patients with relapsed/refractory disease. Emerging data indicate that the context of disease progression after initial treatment with venetoclax may define the success of re-treatment with venetoclax. Specifically, continuous venetoclax exposure may select for resistant disease due to genetic mechanisms such as BCL2 mutations and functional resistance mechanisms such as hyperphosphorylation of BCL-2 family proteins, which decrease the affinity of venetoclax binding to the target or lead to increased MCL-1 dependence and concomitant decrease in BCL-2 dependence. These patients may be best served by switching to a different class of targeted agents at the time of progression. In contrast, relapsed CLL that arises while being off therapy after a period of time-limited venetoclax-based regimens maintains sensitivity to re-treatment with venetoclax for the majority of patients. Novel strategies related to therapeutic targeting of apoptosis include next-generation BCL-2 inhibitors with improved potency and pharmacokinetic profiles, direct targeting of anti-apoptotic BH3 family proteins beyond BCL-2 such as MCL-1, and indirect targeting of MCL-1 through mechanisms such as small molecule cyclin-dependent kinase 9 inhibitors.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. CLL is a highly heterogeneous disease: some patients may never require therapy and others relapse several times after different therapeutic strategies. Therefore, in CLL, prognostic markers are essential to capture high-risk patients for different clinical endpoints including early treatment requirement, early progression after BTK or BCL2 inhibitors and Richter transformation. In early stage CLL, different biological and clinical biomarkers have been identified to predict time to treatment requirement that could be used to identify the most appropriate population for early intervention clinical trial. However, at the moment, the standard of care for early stage CLL remains watch & wait since no survival benefit has been identified in clinical trials with chemoimmunotherapy and with BTK inhibitors. In patients requiring treatment TP53 disruptions identify high-risk patients who benefit the most from long-term continuous therapy with BTKi. On the opposite side of the spectrum, IGHV mutated patients devoid of TP53 disruption benefit the most from fixed-duration therapy with venetoclax-obinutuzumab. In between, the highly heterogenous subgroup of patients with IGHV unmutated genes represents the group in which further efforts are needed to identify additional prognostic biomarkers aimed at selecting patients who can benefit from fixed-duration and patients who can benefit from long term BTKi therapy. In the context of the aggressive transformation of CLL, namely Richter syndrome, the clonal relationship to the CLL counterpart represents the strongest prognostic biomarker. Clonally related Richter syndrome still represents an unmet clinical need which requires further efforts to identify new therapeutic strategies.

Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL. Such findings have the potential to impact patient care through risk stratification, treatment selection and drug discovery. However, this molecular map remains incomplete, with extant questions concerning the origin of the B-cell clone, the role of the TME, inter- and intra-compartmental heterogeneity and of therapeutic resistance mechanisms. Through the application of multi-modal single-cell technologies across tissues, disease states and clinical contexts, these questions can now be addressed with the answers holding great promise of generating translatable knowledge to improve patient care.