Immunology 101: fundamental immunology for the practicing hematologist

From an evolutionary perspective, the immune system developed primarily to protect the host from pathogens. In the continuous balance between killing pathogens and protecting host tissues, selective pressures have shaped the discriminatory functions of the immune system. In addition to protection against microbial pathogens, the immune system also plays a critical role in antitumor immunity. Immune dysfunction, either under- or overactivity, is found in a wide range of hematologic disorders. Here we review the fundamental features of the immune system and the key concepts critical to understanding the impact of immune dysfunction on hematologic disorders.

Induced Pluripotent Stem Cells as a Tool for Modeling Hematologic Disorders and as a Potential Source for Cell-Based Therapies

The breakthrough in human induced pluripotent stem cells (hiPSCs) has revolutionized the field of biomedical and pharmaceutical research and opened up vast opportunities for drug discovery and regenerative medicine, especially when combined with gene-editing technology. Numerous healthy and patient-derived hiPSCs for human disease modeling have been established, enabling mechanistic studies of pathogenesis, platforms for preclinical drug screening, and the development of novel therapeutic targets/approaches. Additionally, hiPSCs hold great promise for cell-based therapy, serving as an attractive cell source for generating stem/progenitor cells or functional differentiated cells for degenerative diseases, due to their unlimited proliferative capacity, pluripotency, and ethical acceptability. In this review, we provide an overview of hiPSCs and their utility in the study of hematologic disorders through hematopoietic differentiation. We highlight recent hereditary and acquired genetic hematologic disease modeling with patient-specific iPSCs, and discuss their applications as instrumental drug screening tools. The clinical applications of hiPSCs in cell-based therapy, including the next-generation cancer immunotherapy, are provided. Lastly, we discuss the current challenges that need to be addressed to fulfill the validity of hiPSC-based disease modeling and future perspectives of hiPSCs in the field of hematology.

Role of Partial Splenectomy in Hematologic Childhood Disorders

The spleen is a secondary lymphoid organ that belongs to the reticular-endothelial system, directly connected to blood circulation. The spleen is greatly involved in the immune response, especially against capsulated bacteria. Splenectomy plays a fundamental role in the treatment of numerous pediatric hematologic disorders. Taking into account all the possible complications (especially infections) linked to this procedure, alternatives to total splenectomy have been sought. Partial splenectomy has been proposed as a treatment that allows the reduction of infectious risk. This approach has proven safe and feasible in most patients, but multicentric and prospective studies are necessary to more accurately define the indications for performing partial splenectomy. However, vaccinations and antibiotic prophylaxis remain fundamental for preventing serious infections, even in the case of partial splenectomy. We review anatomical and functional properties of the spleen, with a focus on medical or surgical indications to splenectomy, aiming to give practical educational information to patients and their families after splenectomy. Furthermore, we discuss the feasibility of partial splenectomy in children with hematologic diseases who require splenectomy.

ATHN Transcends: A Natural History Cohort Study of the Safety, Effectiveness and Practice of Treatment in People with Non-Neoplastic Hematologic Disorders

Background: Clinical researchers affiliated with the American Thrombosis and Hemostasis Network (ATHN) conduct multi-institutional, observational cohort studies assessing the safety and effectiveness of various interventions for people affected by bleeding and clotting disorders. In parallel with the growth of ATHN's clinical studies, the number of new therapies for all congenital and acquired hematologic conditions, not just those for bleeding and clotting disorders, is increasing. Some of the recently FDA-approved therapies for congenital and acquired hematologic conditions have yet to demonstrate long-term safety and effectiveness. In addition, results from well-controlled, pivotal studies often cannot be replicated once a therapy has been approved for general use. With this explosion of potential new therapies on the horizon, it is imperative that clinicians and clinical researchers in the field of non-neoplastic hematology have a uniform, secure, unbiased, and enduring method to collect long-term safety and efficacy data. The overarching objective of ATHN Transcends (NCT04398628) is to characterize the safety, effectiveness, and practice of treatments for all people with congenital and acquired hematologic disorders in the United States. Study Design and Methods: ATHN Transcends is a longitudinal, natural history, observational cohort study being conducted at approximately 150 ATHN-affiliated sites (ATHN Affiliate Network). Participants will be followed for a minimum of 15 years. Specific data will be collected for participants enrolled in cohort-specific arms. Each participant will be assigned in a single cohort: Hemophilia, Von Willebrand Disease, Congenital Platelet Disorder, Rare Bleeding Disorders, Bleeding Not Otherwise Specified, Thrombosis/Thrombophilia, or Non-Neoplastic Hematologic Conditions (see Figure 1). Inclusion criteria include: any age, any congenital or acquired non-neoplastic hematologic disorder, having a bleeding phenotype with an unknown diagnosis, or having a connective tissue disorder with a bleeding tendency. Exclusion criteria include not qualifying for a cohort and the unwillingness or inability to give informed consent or assent. Data will be collected at baseline, every three months, annually and at study exit (Figure 2). Participant biologic samples will be collected at enrollment and yearly thereafter. Safety endpoints mirror those collected by the European Haemophilia Safety Surveillance and include allergic and other acute events, treatment-emergent side effects of therapy, transfusion-transmitted infections, inhibitor development, thrombosis and cardiovascular events, malignancies, neurologic events, and deaths. Adverse events of special interest including thrombotic microangiopathies, anti-drug antibodies, unanticipated bleeding, and hospitalizations will be collected. A panel of patient-reported outcomes (Table 1) will be collected at baseline and annually. Descriptive statistics will be calculated to analyze the primary and secondary outcomes. If there are questions involving multiple cohorts, given there is adequate power to make comparisons between cohorts, for a discrete outcome, we will report estimated difference in percentage between cohorts as well as the 95% confidence interval (CI) of such a difference. If the outcome measurement is a continuous variable, we will report the mean difference and its associated 95% CI. Discussion: The key advantages of an independent study conducted by the ATHN Affiliate Network include the ability to observe participants on a variety of treatment regimens regardless of regimen dosing, frequency, or time of initiation; the ability to observe participants on recently FDA-approved therapies as well as continued monitoring of well-established therapies; the ability to enrich the ATHNdataset; and the ability to be the initial cohort study involving potentially all ATHN-affiliated sites to provide the infrastructure for all congenital and acquired hematologic disorders-related sub-studies in cooperation with other funders, including federal, foundation, academic and industry sources. ATHN Transcends received central institutional review board approval in April 2020. The protocol is currently being rolled out throughout the ATHN Affiliate Network. Figure 1 Figure 1. Disclosures Malec: HEMA Biologics: Consultancy; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy; CSL Behring: Consultancy; Takeda: Consultancy. Recht: uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment.

Cost of Care of Rare Hematologic Disorders in the United States: Call to Action for Policy Supporting Pharmacologic Innovation

BACKGROUND: Rare diseases (RD) present a societal concern because of lack of treatment availability and difficulty developing new treatments. Even when treatment options exist, there are considerable barriers to diagnosis and access to specialty care. OBJECTIVES: To estimate direct (attributable to patient care), indirect (patients' and caregivers' loss of productivity), and mortality-related costs of 5 rare hematologic disorders (atypical hemolytic uremic syndrome [aHUS], acute intermittent porphyria, acquired aplastic anemia, beta thalassemia major, and sickle cell disease) and evaluate burden of care, both when treatment is available and when no treatment exists. We compared these costs with mass market (MM) diseases, including a common hematologic disorder, deep vein thrombosis (DVT), to highlight the need to better serve RD individuals. METHODS: We evaluated peer-reviewed published articles and databases (e.g., Orphanet, the Genetic and Rare Disease Information Center, NORD, NIH), conducted interviews with patient advocacy groups (e.g., Global Gene, the EveryLife Foundation for Rare Diseases, NORD) and key opinion leaders (e.g., Penn Blood Disorders Center), and referred to the US Bureau of Labor Statistics and Medi-Span Price Rx. We performed a statistical analysis to confirm that the sample size of patients covered in our disease selection was significant. In-depth analyses were performed to assess the per patient per year (PPPY) direct, indirect, and mortality costs associated with the 5 disorders, as well as costs for MM diseases, including DVT. While treatments exist for each of these 5 rare disorders, there are no universal curative options. Cost data for MM diseases, including DVT, were derived from literature reviews. RESULTS: The economic burden of rare hematologic disorders in the US is considerable. For most diseases, treatment costs account for the majority of total direct costs (52-90%). Indirect and mortality costs account for 4% and 22% of the total burden cost, respectively, but mortality costs vary widely (4-74% of total costs). Highest overall direct cost observed was for aHUS ($530k) due to challenging diagnosis, persistent treatment, and poor prognosis. Productivity loss is 2 hours/week for patients and 2-4 hours/week for caregivers. The life expectancy of aHUS patients is ~60 years, but if untreated this may be shortened to ~35 years. The lowest overall direct cost was for beta thalassemia major ($69k). The majority of direct costs are split between treatment costs and medical procedures. Patient productivity loss is estimated to be >3.5 weeks of work loss/year in the 60% of patients who require bimonthly transfusions. Caregiver burden constitutes 9.2 hours/week of work loss. New therapies are likely to offset mortality costs in the future. Although the direct, indirect, and mortality costs of these 5 disorders are high (average total cost $228k), the burden of cost is higher in all scenarios if treatments did not exist (60% increase in overall cost). As would be expected under the "no treatment" scenarios, the direct costs attributed to each disease decreased, but indirect and mortality costs increased. Value of treatment is demonstrated by decreases in PPPY indirect costs. When no treatments were available, the range for productivity loss was ~$33k to $61k for patients and ~$25k to $61k for caregivers, compared with ~$3k to $22k for patients and ~$4k to $5k for caregivers when treatments were available. The average PPPY costs of MM diseases for which treatments are available, including DVT, are estimated to be between $6k to $27k for direct costs, $10k to $16k for indirect costs, and $3k to $24k for mortality costs. In comparison with MM diseases, including DVT, the 5 rare disorders had average direct costs of ~$169k (a 6.25- to 26-fold increase), indirect costs of ~$9k (a modest decrease), and mortality costs of ~$50k (a 2.1- to 15-fold increase). CONCLUSIONS: These scenario analyses demonstrate that RD therapies generate positive economic value. Further, analysis shows that RD pose a greater social economic burden than MM diseases. This information can be utilized to further efforts by the RD community for increased governmental investment in RD treatment, diagnosis, and access. Disclosures Andreu Perez: Chiesi Global Rare Diseases: Other: PA is a full-time employee IQVIA. The employer of PA received consulting fees from Chiesi Global Rare Diseases for this analysis. Cioffi: Chiesi Global Rare Diseases: Current Employment. Karam: Chiesi Global Rare Diseases: Other: JK is a full-time employee IQVIA. The employer of JK received consulting fees from Chiesi Global Rare Diseases for this analysis. Child: Chiesi Global Rare Diseases: Other: CC is a full-time employee IQVIA. The employer of CC received consulting fees from Chiesi Global Rare Diseases for this analysis. Tricta: Chiesi Canada Corp: Current Employment. Chiesi: Chiesi Farmaceutici SpA: Current Employment.

Current Trends in the Gene Therapy of Hematologic Disorders

Recent advances in molecular genetics and the invention of new technologies led to an advance in the development of gene therapy. Gene therapy is used to correct defective genes in order to cure a disease or help the body better fight a disease. It works by restoring or modifying cellular functions through the introduction of a functional gene into the target cell. The concept of gene therapy is simple, but introducing it to routine clinical practice is not. The main concerns are related to some safety issues as well as to the problem that maintaining a stable and prolonged expression in target cells may not be easily achieved. In spite of the difficulties, gene therapy remains a hope for many hematological disorders that cannot be effectively treated so far. This article reviews the current status of gene therapy with a focus on hematological disorders. In addition, clinically applied approaches are presented through particular examples of approved gene therapy drugs.

Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation (“watch and wait”) may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.