Clinical Applications of Gene Therapy for Immuno-Deficiencies
Yashwant Pathak in Gene Delivery, 2022
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].
Hairy Cell Leukemia
Dongyou Liu in Tumors and Cancers, 2017
Patients with HCL may be asymptomatic, and the disease is discovered on a routine checkup. Alternatively, patients manifest symptoms associated with cytopenias such as opportunistic infections, fatigue, bleeding, and/or abdominal discomfort due to the spleen enlargement. Other rare manifestations are cutaneous and bone lytic lesions, gastrointestinal or central nervous system involvement, and/or autoimmune disorders. Peripheral lymphadenopathy is very rare, but around 10%–15% of patients may have abdominal lymphadenopathy. Therefore, CT scan is recommended in the diagnostic and staging workup. The blood counts show variable degrees of anemia, thrombocytopenia, and neutropenia. Macrocytosis is frequent, and monocytopenia is characteristic in active HCL. Most cases have a few circulating lymphocytes with the morphology of hairy cells. Liver function tests may show a raised alkaline phosphatase that often correlates with liver involvement by the disease. In addition to the diagnostic tests on blood and bone marrow, the European Society for Medical Oncology (ESMO) guidelines recommend the following investigations for a staging workup: full blood counts with differential and reticulocytes, liver and renal biochemistry, serum immunoglobulins, B2 microglobulin, direct antiglobulin test (DAT), hepatitis B and C serology, and CT scan of the chest, abdomen, and pelvis [5].
Principles of Clinical Pathology
Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018
Preparation of bone marrow smears at necropsy is a common practice in most nonclinical studies, but bone marrow smear examination is rarely indicated. Routine hematology tests reflect bone marrow function, and if results from these tests are unaffected or only slightly affected, bone marrow smear examination has little or no benefit. In addition, bone marrow smear examination has no value if mechanisms for more pronounced hematology findings are clear from peripheral blood data and other findings. When indicated by one or more relatively pronounced peripheral blood cytopenias with no apparent etiology (e.g., the test article is not a cytotoxic chemotherapeutic), or by unusual peripheral blood cell morphologic abnormalities, bone marrow smear examination can assess the relative numbers, maturation, and appearance of precursor cells in order to help explain the peripheral blood changes (see Chapter 15, Hematopoietic System). Evaluation of histologic sections of the bone marrow is necessary to fully appreciate changes in cellularity.
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).
Mixed chimerism after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia
Published in Hematology, 2021
Yuling Zhang, Yumiao Li, Liangliang Wu, Ming Zhou, Caixia Wang, Wenjian Mo, Xiaowei Chen, Shilin Xu, Ruiqing Zhou, Shunqing Wang, Yuping Zhang
Chimerism evaluation was performed monthly in the first 3 months, every 3 months between 3 months and 1 year, and every 6 months after 1 year from allo-HSCT using bone marrow or peripheral blood mononuclear cell. If a decrease in the PB cell count was detected during the follow-up, chimerism evaluation was then performed at any time. When the sex was different between the patient and the donor, fluorescence in situ hybridization and microsatellite DNA fingerprinting (also known as short tandem repeat) were used to detect chimerism. When the sex was the same, only microsatellite DNA fingerprinting was used for detection. DC was defined as >95% of donor cells, MC as 5-95% of recipient cells, and GF was defined as <5% of donor cells detected at any time following HSCT. The level of MC was classified based on the percentage of residual host cells (RHCs) in the PBs (level 1, <10% RHCs; level 2, 10-25% RHCs; level 3, >25% RHCs). Cytopenia was defined as fluctuating blood count and no recovery following treatment (specifically, neutrophil count <0.5 × 109, granulocyte stimulating factor treatment ineffective for 2 weeks, platelet count <20 × 109, infusion and other treatments ineffective for 2 weeks, hemoglobin concentration <60 g/l and no increase in the infusion and other treatments for 2 weeks). Finally, according to the percentage of donor-recipient chimerism and the presence or absence of cytopenia, patients with AA were divided into the following four groups: Group 1, DC; group 2, MC without cytopenia; group 3, MC with cytopenia; group 4, SGF.
Blood product administration during high risk neuroblastoma therapy
Published in Pediatric Hematology and Oncology, 2020
Allison Silverstein, Kiranmye Reddy, Valeria Smith, Jennifer H. Foster, Heidi V. Russell, Sarah B. Whittle
Patients with HR NB regularly require packed red blood cell (pRBC) and platelet transfusions as supportive care for anemia and thrombocytopenia. The causes of their cytopenias are multi-factorial, including bone marrow infiltration by NB, myelosuppression from chemotherapy or radiotherapy, decreased production from chronic disease, nutritional deficiencies, and blood loss.9,10 Clinical trials report on the frequency of cytopenias using the US National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). This method of reporting, however, does not capture the frequency of blood product transfusions. Nor does CTCAE grading reflect symptomatology or institutional transfusion thresholds, making it impossible to determine the number of transfusions administered from these data.11–13
Related Knowledge Centers
- Anemia
- Blood Cell
- White Blood Cell
- Platelet
- Neutrophil
- Neutropenia
- Chemotherapy
- Leukopenia
- Thrombocytopenia
- Radiation Therapy