Cellular Therapy in Chronic Lymphocytic Leukemia: Have We Advanced in the Last Decade?

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy, affecting mainly older adults. Despite the recent introduction of multiple targeted agents, CLL remains an incurable disease. Cellular therapy is a promptly evolving area that has developed over the last decades from such standard of care as hematopoietic cell transplantation (HCT) to the novel treatment modalities employing genetically engineered immune cells. SUMMARY: Tailoring the proper treatment for each patient is warranted and should take into account the disease biology, patient characteristics, and the available treatment modalities. Nowadays, the most broadly applied cellular therapies for CLL management are HCT and chimeric antigen receptor-T (CAR-T) cells. However, CAR-T cell therapy is currently not yet approved in CLL, and the appropriate sequencing for the administration of these agents remains to be clarified. KEY MESSAGES: The current review will discuss various available cellular treatment options, their advances and limitations, as well as the optimal timing for the employment of such therapies in CLL patients.

Eosinophilic Pleocytosis in the Cerebrospinal Fluid following CAR-T Cell Therapy for Central Nervous System Lymphoma: A Case for Warning?

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapy, emerging as an efficient treatment option for patients with secondary central nervous system (CNS) lymphoma, is frequently complicated with immune effector cell-associated neurotoxicity syndrome (ICANS). CASE PRESENTATION: We report a case of a 64-year-old woman with transformed follicular lymphoma, developing high-grade ICANS with eosinophilic pleocytosis following third-line therapy with CAR-T cells (tisagenlecleucel). During bridging therapy, she declined neurologically and was diagnosed with secondary CNS lymphoma. She received methotrexate-cytarabine-thiotepa-rituximab regimen with clinical and radiological improvement. Post-CAR-T cell infusion she developed cytokine release syndrome grade II and ICANS grade III. Given the lack of response to steroids, anakinra was initiated with complete ICANS resolution. Cerebrospinal fluid (CSF) analysis, performed only on day +10 due to thrombocytopenia, revealed eosinophils, while infections were excluded. CONCLUSION: This report emphasizes the importance of CSF analysis in individuals with CAR-T-related neurotoxicity for elucidating the role of specific immune cells in such complications.

Host effects contributing to cancer therapy resistance.

There are several approaches for the management of malignant disease. However, tumor resistance to therapy is still a major challenge in the clinic. Efflux transporters, genetic responses and enzyme activity in tumor cells are examples of the main modalities that account for resistance to therapy. In addition, emerging evidence suggests that the host also plays a significant role in promoting therapy resistance. Recruitment of different host cell types to the treated tumor site occurs in response to a range of therapies, including chemotherapy, radiation and even targeted drugs. This host response may have a protective effect on the tumor cells, not only negating anti-tumor activity, but also promoting a resistant tumor. In this review, we focus on host-tumor interactions leading to therapy resistance with special emphasis on different host cells and secreted factors within the tumor microenvironment. The development of novel inhibitors that block the host response to therapy could be used as a treatment strategy to enhance therapy outcomes and survival.

Treatment of T cell lymphoblastic lymphoma in children and adolescents: Israel Society of Pediatric Hematology Oncology retrospective study.

BACKGROUND: Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia. OBJECTIVES: To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006. METHODS: We conducted a retrospective multi-institutional, non-randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL-BFM-95 protocol. RESULTS: At a median follow-up of 4 years (range 1-9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five patients (13.5%) relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA). CONCLUSIONS: Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.

Thrombosis in vasculitic disorders-clinical manifestations, pathogenesis and management.

Inflammation and coagulation are known to affect each other in many ways. Vasculitis represents a group of disorders where blood vessels (small, medium, large or variable) are infiltrated with inflammatory cells. Accumulating evidence in the literature suggests both clinical and physiological association between vasculitis and thrombosis. Vasculitis-associated thrombosis involves arteries and veins, and a tight connection has been reported between the activity of vasculitis and the appearance of thrombosis. Pathophysiology of these relations is complex and not completely understood. While thrombophilic factors are associated with vasculitis, it remains unclear whether a true association with clinical thrombosis is present. Furthermore, several factors leading to hemostasis, endothelial injury and induction of microparticles were described as possibly accounting for thrombosis. Management of thrombosis in vasculitis patients is challenging and should be further assessed in randomized controlled studies. The current review describes clinical manifestations, pathogenesis and management of thrombosis associated with different vasculitides.