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Haematological Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
This is chronic progressive haemopoietic failure caused by infiltration of the marrow space by fibrosis. Progressive cytopenias develop and can be severe. Extramedullary spread of haematopoiesis to the spleen produces dramatic and uncomfortable splenomegaly. Transformation to AML is commoner than with other MPNs.
Clinical Applications of Gene Therapy for Immuno-Deficiencies
Published in Yashwant Pathak, Gene Delivery, 2022
Khushboo Faldu, Sakshi Gurbani, Jigna Shah
Hemophagocytic lymphohistiocytosis (HLH) can be fatal. The symptoms include cytopenias, hyper inflammation, splenomegaly, and uncontrolled immune activation [63]. HLH can be caused due to various underlying conditions, like familial hemophagocytic lymphohistiocytosis (FHL), autoimmunity, infection, or malignancy. Defects in the functioning of cytotoxic T- and NK-cells, together with autosomal recessive alterations in syntaxin 11 (STX11), MUNC 13-4 [Protein unc-13 homolog D (UNC13D)], and perforin (PRF1) result in the development of FHL. The most common cause is PRF1 mutations. AlloHSCT is the preferred treatment modality for genetically mutated or relapsed refractory HLH patients [64, 65]. Etoposide, with or without cyclosporine and glucocorticoids, are a part of the standard of care, but lack adequate disease control in 40% of patients [66]. Emapalumab, an anti-interferon gamma (IFNγ) monoclonal antibody, has been approved as second-line therapy for primary HLH in the USA, as IFNγ plays a central role in pathogenesis in HLH, with levels correlating with active disease [67, 68]. Alemtuzumab and Janus kinase (JAK) inhibitors are being tested for improving remission and allowing progress to HSCT [69–74]. Alemtuzumab with corticosteroids and cyclosporine has provided favorable safety and efficacy in children suffering from primary HLH (91.6% survived to alloHSCT) [74]. HSC-GT and T-cell strategies are being developed for the treatment of FHL [75–79].
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Allo-SCT remains the only treatment that can accord long-term remission and a 10-year OS of about 40%. At present, there are no satisfactory non-transplant options, and the principal aim of therapy is to improve symptoms related to cytopenias and proliferative features. HMAs are approved for symptomatic low-risk and all intermediate- and high-risk patients. Response rates appear to be similar to those seen in patients with MDS, with no significant impact on risk of transformation or survival. Based on the poor prognostic impact of plasmacytic dendritic cells and CD123-positivity of clonal monocytes in CMML, tagraxofusp, a CD123-targeted drug, is currently being tested both as a monotherapy and in combination with HMAs or venetoclax.141 The preliminary monotherapy Phase II results are encouraging, with clinical benefits, in particular reduction of splenomegaly, reduction of symptom burden, and reduction of red-cell transfusion requirements; some patients achieved BM CRs and were successfully allografted.
Safety evaluation of axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma
Published in Expert Opinion on Drug Safety, 2023
Karthik Nath, Kitsada Wudhikarn, Ana Alarcon Tomas, Miguel-Angel Perales
There are limited therapeutic interventions for the management of severe cytopenias. Currently, treatment strategies involve transfusion support and supportive cares. However, there are no consensus guidelines for the management of this post-CAR-T complication. Granulocyte-colony stimulating factor (G-CSF) can be used for severe neutropenia from day 14 onwards, following the resolution of CRS/ICANS, due to some concerns about exacerbating these toxicities. Nevertheless, recent data on earlier prophylactic G-CSF found no effect on immunotoxicity, CAR T-cell expansion, or prognosis [107]. Autologous stem cell rescue is another option if stored cells are available and can aid in the recovery of prolonged cytopenias [108]. Anti-inflammatory therapies such as dexamethasone, and erythropoietin stimulating agents/thrombopoietin receptor agonists may also be considered for these patients. Additionally, there have been a few cases where donor-derived, unconditioned CD34-selected ‘top-up’ resulted in hematopoietic recovery, and this might be considered in post-allo-HCT patients. Allo-HCT is a last resort in patients with refractory cytopenias [97]. Due to the increased morbidity and potential mortality associated with hematologic toxicities post CAR T-cell infusion, it would be important to promptly identify patients at high risk for closer monitoring and early initiation of supportive therapies. Prospective studies are warranted to determine the optimal management strategies of this toxicity.
Monoclonal antibodies used for the management of hemataological disorders
Published in Expert Review of Hematology, 2022
Kanjaksha Ghosh, Kinjalka Ghosh
This is a chimeric monoclonal antibody mouse/human used as a complex with a toxin vedotin (MonoMethyl Auristatin E). The antibody is directed to CD30 antigen, a member of the TNF receptor family, and is expressed in several types of cell. The drug is used in relapsed/refractory Hodgkin's lymphoma. Hodgkin's lymphoma relapses after autologous stem cell transplantation and for those relapsed/refractory patients who are ineligible for autologous transplantation or are at a high risk of relapse following transplantation. Similarly, it has been used in peripheral T cell lymphoproliferative disorders, Cutaneous T lymphoproliferative disorders, and in Anaplastic Large cell lymphoma [38–41]. CD30 expression in the malignant cell is a requirement for its use. This is used in combination with other chemotherapy. This medicine should not be used simultaneously with bleomycin. Fatigue, fever, nausea, vomiting, peripheral neuropathy, and prolonged cytopenia are common side effects.
Adenosine Deaminase Type II Deficiency: Severe Chronic Neutropenia, Lymphoid Infiltration in Bone Marrow, and Inflammatory Features
Published in Immunological Investigations, 2022
Merve Süleyman, Çağman Tan, Aysegul Uner, Çağkan İnkaya, Selin Aytaç, Yahya Büyükaşık, Kaan Boztug, İlhan Tezcan, Deniz Cagdas
Pure red cell anemia is a common presentation of DADA2 (Hashem et al. 2017a). Hematologic problems such as cytopenia, especially severe anemia requiring transfusion and neutropenia may be seen. The presentation may mimic hematopoietic neoplasms, such as MDS, like in P1 and P2. Immunological features varies from severe neutropenia, autoimmunity, lymphoproliferation to cellular immunodeficiency leading to severe infections (Van Eyck et al. 2015). In some cases, lymphopenia may be prominent and this leads to severe viral infections, such as HHV-6, adenovirus, norovirus and polyomavirus (Van Eyck et al. 2015). In some, neutropenia is prominent, and may lead to severe subcutaneous infections including myositis. Severe neutropenia has been reported in up to 10% of patients (Meyts and Aksentijevich 2018). Additionally, neutropenia may be the first clinical finding of DADA2 or accompanied with other manifestations during follow-up (Cipe et al. 2018). Both P1 and P2 had severe neutropenia and their neutropenia developed later in life. They were both considered to have MDS. Bone marrow infiltration with reactive CD3+ lymphocytes and diffuse fibrosis were observed. Similarly, Hsu et al. previously reported increased T-cells with lymphohistiocytic aggregates in DADA2 patients (Hsu et al. 2016).