Summary
Lymphoblastic lymphoma (LBL) is the second most common type of Non‐Hodgkin Lymphoma (NHL) in childhood and adolescence, accounting for 25–35% of all cases. The majority, 70–80%, is of ...T‐lymphoblastic origin while 20–25% arise from B lymphoblasts. With current therapy, the event‐free and overall survivals for paediatric LBL patients now exceeds 80%. Therapy, especially in T‐LBL with large mediastinal tumours, is challenging, with both significant morbidity and late sequela. An additional challenge is the dismal prognosis of patients with refractory or relapsed disease. This review article will focus on the growing knowledge of the pathogenesis and biology of LBL, recent advances and challenges in the therapy of LBL, and ongoing and future efforts and opportunities in optimizing therapy and developing novel targeted treatment approaches.
Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary ...(smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.
Neurodegeneration is a devastating complication of Langerhans cell histiocytosis (LCH), but it is not clear how it develops. In this issue of Immunity, Wilk et al. demonstrate that circulating ...BRAFV600E
myeloid cells damage the blood-brain barrier and infiltrate the brain. Dual inhibition of the MAPK and senescence pathways can block parenchymal injury, providing a potential therapeutic avenue for histiocytic neurodegeneration.
Regulation of tyrosine phosphorylation is a critical control point for
integration of environmental signals into cellular responses. This regulation
is mediated by the reciprocal actions of protein ...tyrosine kinases and
phosphatases. CD45, the first and prototypic receptor-like protein tyrosine
phosphatase, is expressed on all nucleated hematopoietic cells and plays a
central role in this process. Studies of CD45 mutant cell lines, CD45-deficient
mice, and CD45-deficient humans initially demonstrated the essential role of
CD45 in antigen receptor signal transduction and lymphocyte development. It is
now known that CD45 also modulates signals emanating from integrin and cytokine
receptors. Recent work has focused on regulation of CD45 expression and
alternative splicing, isoform-specific differences in signal transduction, and
regulation of phosphatase activity. From these studies, a model is emerging in
which CD45 affects cellular responses by controlling the relative threshold of
sensitivity to external stimuli. Perturbation of this function may contribute
to autoimmunity, immunodeficiency, and malignancy. Moreover, recent advances
suggest that modulation of CD45 function can have therapeutic benefit in many
disease states.
Glucocorticoid (GC) resistance is a poor prognostic factor in T‐cell acute lymphoblastic leukaemia (T‐ALL). Interleukin‐7 (IL‐7) mediates GC resistance via GC‐induced upregulation of IL‐7 receptor ...(IL‐7R) expression, leading to increased pro‐survival signalling. IL‐7R reaches the cell surface via the secretory pathway, so we hypothesized that inhibiting the translocation of IL‐7R into the secretory pathway would overcome GC resistance. Sec61 is an endoplasmic reticulum (ER) channel that is required for insertion of polypeptides into the ER. Here, we demonstrate that KZR‐445, a novel inhibitor of Sec61, potently attenuates the dexamethasone (DEX)‐induced increase in cell surface IL‐7R and overcomes IL‐7‐induced DEX resistance.
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of ...features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, “HLH disease” should be distinguished from “HLH disease mimics” and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of “primary” and “secondary.” We provide expert‐based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.
As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are ...clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.
•Daratumumab is effective against T-ALL in human xenograft models.•CD38 is a novel target with broad potential in the treatment of T-ALL.
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