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Drugs Jul 2023Glofitamab (Columvi) is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody being developed by Roche for the treatment of B-cell non-Hodgkin lymphomas,... (Review)
Review
Glofitamab (Columvi) is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody being developed by Roche for the treatment of B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma (DLBCL). Glofitamab received its first approval (with conditions) on 25 March 2023, in Canada, for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, DLBCL arising from follicular lymphoma, or primary mediastinal B-cell lymphoma, who have received two or more lines of systemic therapy and are ineligible to receive or cannot receive CAR T-cell therapy or have previously received CAR T-cell therapy. Glofitamab is also under regulatory review for relapsed or refractory DLBCL in the EU and USA and in April 2023 received a positive opinion recommending the granting of a conditional marketing authorization in the EU. Clinical development of glofitamab, as a monotherapy and in combination with other agents for the treatment of non-Hodgkin lymphomas, is continuing worldwide. This article summarizes the milestones in the development of glofitamab leading to this first approval for relapsed or refractory DLBCL.
Topics: Adult; Humans; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Immunotherapy, Adoptive
PubMed: 37285013
DOI: 10.1007/s40265-023-01894-5 -
Annals of the Rheumatic Diseases Oct 2023Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most...
The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
OBJECTIVE
Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the of diagnosis, treatment and monitoring of HLH/MAS.
METHODS
A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS.
RESULTS
The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance.
CONCLUSION
These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
Topics: Child; Adult; Humans; United States; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Rheumatology; Consensus
PubMed: 37487610
DOI: 10.1136/ard-2023-224123 -
European Journal of Cancer (Oxford,... Dec 2023On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated... (Review)
Review
On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.
Topics: Humans; Mycosis Fungoides; Sezary Syndrome; Consensus; Quality of Life; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms; Immunologic Factors
PubMed: 37890355
DOI: 10.1016/j.ejca.2023.113343 -
Current Allergy and Asthma Reports Jul 2023Neurosarcoidosis is a rare manifestation of sarcoidosis that is challenging to diagnose. Biopsy confirmation of granulomas is not sufficient, as other granulomatous... (Review)
Review
PURPOSE OF REVIEW
Neurosarcoidosis is a rare manifestation of sarcoidosis that is challenging to diagnose. Biopsy confirmation of granulomas is not sufficient, as other granulomatous diseases can present similarly. This review is intended to guide the clinician in identifying key conditions to exclude prior to concluding a diagnosis of neurosarcoidosis.
RECENT FINDINGS
Although new biomarkers are being studied, there are no reliable tests for neurosarcoidosis. Advances in serum testing and imaging have improved the diagnosis for key mimics of neurosarcoidosis in certain clinical scenarios, but biopsy remains an important method of differentiation. Key mimics of neurosarcoidosis in all cases include infections (tuberculosis, fungal), autoimmune disease (vasculitis, IgG4-related disease), and lymphoma. As neurosarcoidosis can affect any part of the nervous system, patients should have a unique differential diagnosis tailored to their clinical presentation. Although biopsy can assist with excluding mimics, diagnosis is ultimately clinical.
Topics: Humans; Biopsy; Central Nervous System Diseases; Granuloma; Sarcoidosis
PubMed: 37256482
DOI: 10.1007/s11882-023-01092-z -
Cancer Discovery Sep 2023CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to...
UNLABELLED
CAR T-cell product quality and stemness (Tstem) are major determinants of in vivo expansion, efficacy, and clinical response. Prolonged ex vivo culturing is known to deplete Tstem, affecting clinical outcome. YTB323, a novel autologous CD19-directed CAR T-cell therapy expressing the same validated CAR as tisagenlecleucel, is manufactured using a next-generation platform in <2 days. Here, we report the preclinical development and preliminary clinical data of YTB323 in adults with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL; NCT03960840). In preclinical mouse models, YTB323 exhibited enhanced in vivo expansion and antitumor activity at lower doses than traditionally manufactured CAR T cells. Clinically, at doses 25-fold lower than tisagenlecleucel, YTB323 showed (i) promising overall safety [cytokine release syndrome (any grade, 35%; grade ≥3, 6%), neurotoxicity (any grade, 25%; grade ≥3, 6%)]; (ii) overall response rates of 75% and 80% for DL1 and DL2, respectively; (iii) comparable CAR T-cell expansion; and (iv) preservation of T-cell phenotype. Current data support the continued development of YTB323 for r/r DLBCL.
SIGNIFICANCE
Traditional CAR T-cell manufacturing requires extended ex vivo cell culture, reducing naive and stem cell memory T-cell populations and diminishing antitumor activity. YTB323, which expresses the same validated CAR as tisagenlecleucel, can be manufactured in <2 days while retaining T-cell stemness and enhancing clinical activity at a 25-fold lower dose. See related commentary by Wang, p. 1961. This article is featured in Selected Articles from This Issue, p. 1949.
Topics: Mice; Animals; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Cell Culture Techniques; Antigens, CD19
PubMed: 37249512
DOI: 10.1158/2159-8290.CD-22-1276 -
Frontiers in Immunology 2023Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a humanized monoclonal antibody targeting the cell surface receptor CD22 coupled to a cytotoxic... (Review)
Review
Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a humanized monoclonal antibody targeting the cell surface receptor CD22 coupled to a cytotoxic calicheamicin payload an acid labile linker. InO has shown significant activity in relapsed and refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in both single agent and combination chemotherapy regimens in adult and pediatric trials. Its use in newly diagnosed elderly patients has also been established while clinical trials investigating its use in newly diagnosed pediatric patients and fit adults are ongoing. Notable toxicities include sinusoidal obstruction syndrome (SOS), particularly in patients who undergo hematopoietic stem cell transplantation (HSCT) after InO as well as myelosuppression and B-cell aplasia which confer increased infection risk, particularly in combination with cytotoxic chemotherapy. In the relapsed/refractory (R/R) setting, the planned subsequent curative therapy modality must be considered when using InO to mitigate SOS risk if proceeding to HSCT and account for potential B-cell aplasia if proceeding to chimeric antigen receptor CAR-T therapy. Studies exploring mechanisms of resistance or failure of InO are ongoing but modulation or loss CD22 expression, alternative CD22 splicing, and high Bcl-2 expression have been implicated. In this review, we will summarize the currently available data on InO, with an emphasis on pediatric trials, and explore future directions including combinatorial therapy.
Topics: Adult; Aged; Humans; Child; Inotuzumab Ozogamicin; Burkitt Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Monoclonal, Humanized; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37600823
DOI: 10.3389/fimmu.2023.1237738 -
Blood Reviews Jul 2023Large Granular Lymphocyte (LGL) Leukemia is a rare, heterogeneous even more that once thought, chronic lymphoproliferative disorder characterized by the clonal expansion... (Review)
Review
Large Granular Lymphocyte (LGL) Leukemia is a rare, heterogeneous even more that once thought, chronic lymphoproliferative disorder characterized by the clonal expansion of T- or NK-LGLs that requires appropriate immunophenotypic and molecular characterization. As in many other hematological conditions, genomic features are taking research efforts one step further and are also becoming instrumental in refining discrete subsets of LGL disorders. In particular, STAT3 and STAT5B mutations may be harbored in leukemic cells and their presence has been linked to diagnosis of LGL disorders. On clinical grounds, a correlation has been established in CD8+ T-LGLL patients between STAT3 mutations and clinical features, in particular neutropenia that favors the onset of severe infections. Revisiting biological aspects, clinical features as well as current and predictable emerging treatments of these disorders, we will herein discuss why appropriate dissection of different disease variants is needed to better manage patients with LGL disorders.
Topics: Humans; Leukemia, Large Granular Lymphocytic; Killer Cells, Natural; Mutation; Leukemia; Neutropenia
PubMed: 36870881
DOI: 10.1016/j.blre.2023.101058