Cost Utility of Lifelong Immunoglobulin Replacement Therapy vs Hematopoietic Stem Cell Transplant to Treat Agammaglobulinemia.

Importance: Lifelong immunoglobulin replacement therapy (IRT) is standard-of-care treatment for congenital agammaglobulinemia but accrues high annual costs ($30 000-$90 000 per year) and decrements to quality of life over patients' life spans. Hematopoietic stem cell transplant (HSCT) offers an alternative 1-time therapy, but has high morbidity and mortality. Objective: To evaluate the cost utility of IRT vs matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT to treat patients with agammaglobulinemia in the US. Design, Setting, and Participants: This economic evaluation used Markov analysis to model the base-case scenario of a patient aged 12 months with congenital agammaglobulinemia receiving lifelong IRT vs MSD or MUD HSCT. Costs, probabilities, and quality-of-life measures were derived from the literature. Microsimulations estimated premature deaths for each strategy in a virtual cohort. One-way sensitivity and probabilistic sensitivity analyses evaluated uncertainty around parameter estimates performed from a societal perspective over a 100-year time horizon. The threshold for cost-effective care was set at $100 000 per quality-adjusted life-year (QALY). This study was conducted from 2020 across a 100-year time horizon. Exposures: Immunoglobulin replacement therapy vs MSD or MUD HSCT for treatment of congenital agammaglobulinemia. Main Outcomes and Measures: The primary outcomes were incremental cost-effectiveness ratio (ICER) expressed in 2020 US dollars per QALY gained and premature deaths associated with each strategy. Results: In this economic evaluation of patients with congenital agammaglobulinemia, lifelong IRT cost more than HSCT ($1 512 946 compared with $563 776 [MSD] and $637 036 [MUD]) and generated similar QALYs (20.61 vs 17.25 [MSD] and 17.18 [MUD]). Choosing IRT over MSD or MUD HSCT yielded ICERs of $282 166 per QALY gained over MSD and $255 633 per QALY gained over MUD HSCT, exceeding the US willingness-to-pay threshold of $100 000/QALY. However, IRT prevented at least 2488 premature deaths per 10 000 microsimulations compared with HSCT. When annual IRT price was reduced from $60 145 to below $29 469, IRT became the cost-effective strategy. Findings remained robust in sensitivity and probabilistic sensitivity analyses. Conclusions and Relevance: In the US, IRT is more expensive than HSCT for agammaglobulinemia treatment. The findings of this study suggest that IRT prevents more premature deaths but does not substantially increase quality of life relative to HSCT. Reducing US IRT cost by 51% to a value similar to IRT prices in countries implementing value-based pricing may render it the more cost-effective strategy.

Prevalence of hypogammaglobulinemia and its management with subcutaneous immunoglobulin supplementation in patients after allogeneic hematopoietic stem cell transplantation-a single-center analysis.

Secondary immunodeficiencies are frequently observed after allo-HSCT. The efficacy of subcutaneous IgG preparations in this population is unknown. A retrospective single-institution study involved 126 adult patients transplanted in 2012-2019 for hematological malignancies. Patients were tested every 2-3 weeks for plasma IgG concentration during the 1st year after transplantation and supplemented with facilitated subcutaneous immunoglobulin when they either had IgG concentration < 500 mg/dl or between 500 and 700 mg/dl and recurrent infection. The IgG concentration < 500 mg/dL was diagnosed in 41 patients, while 500-700 mg/dL in 25 and altogether 53 patients received IgG supplementation. The median number of IgG administrations was 2. The median time to the first IgG administration after allo-HSCT was 4.1 months, while to the next administration (if more than one was required) 53 days (prophylactic group) and 32 days (group with infections). We did not observe any significant toxicity. Two situations were associated with increased probability of meeting criteria for IgG supplementation: diagnosis of either acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL) (83.8% versus 39.3% for other diagnosis, p = 0.000) and the systemic use of corticosteroids (64.2% versus 31.5% for patients without systemic corticosteroids, p = 0.005). Over 40% of the adult recipients may require at least incidental immunoglobulin supplementation during the first year after allo-HSCT. Low IgG concentrations are associated with inferior outcomes. The subcutaneous route of IgG administration appeared to be safe and may allow for long persistence.

Agammaglobulinemia: Epidemiology, Pathogenesis, Clinical Phenotype, Diagnosis, Prognosis and Management.

Agammaglobulinemia is a type of primary antibody deficiencies, characterized by severe reduction in serum level of all types of immunoglobulins level and absence of B cells in the peripheral blood. X-linked and various autosomal recessive/dominant mutations have been identified underlying the pathogenesis of this disorder. Affected patients present a broad range of clinical manifestations, including respiratory infections, gastrointestinal complications, Enterovirus infections, autoimmunity, and malignancies. This disease can be controlled by different therapeutic strategies. In this review, we describe different aspects of agammaglobulinemia such as epidemiology, pathogenesis, clinical phenotype, diagnosis, management, and prognosis of congenital agammaglobulinemia.

Treosulfan-based reduced toxicity hematopoietic stem cell transplantation in X-linked agammaglobulinemia: A cost-effective alternative to long-term immunoglobulin replacement in developing countries.

X-linked agammaglobulinemia (XLA) is a primary antibody disorder due to a mutation in the Bruton tyrosine kinase gene that requires lifelong immunoglobulin replacement resulting in a significant economic burden and treatment abandonment. Hematopoietic stem cell transplantation (HSCT) offers an alternative option for complete cure. In our series, two children with XLA underwent successful HSCT using a myeloablative conditioning with thiotepa, treosulfan, and fludarabine from a matched sibling donor. The second child had rejected his first graft following a busulfan-based regimen with resultant autologous reconstitution. At 6 months post-HSCT, serum IgG were normal, off IVIG, and had no infections. Both children after a median follow-up of 20 months have 100% chimerism. Treosulfan-based reduced toxicity myeloablative HSCT has encouraging results with a positive impact on the socioeconomics in developing countries.

Personalized Therapy: Immunoglobulin Replacement for Antibody Deficiency.

Immunoglobulin replacement therapy is the cornerstone of management for most primary immunodeficiency disease patients. The selection of a particular product, dose, and route of administration requires an understanding of the features of therapeutic immunoglobulin as well as patient-specific risk factors in order to maximize efficacy and tolerability and minimize risk. Individualizing therapy, taking into consideration the burdens of care, is necessary in order to optimize patient outcomes.

Investor Outlook: Rising from the Ashes; GSK's European Approval of Strimvelis for ADA-SCID.

GlaxoSmithKline's (GSK) and partner San Raffaele Telethon Institute for Gene Therapy's recent positive European approval for Strimvelis for treatment of severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) represents the second EU-approved gene therapy and the first γ-retrovirus and first ex vivo gene therapy. In this article we discuss the significance and implications of this historic approval for the broader gene therapy field.

Modeling primary immunodeficiency disease epidemiology and its treatment to estimate latent therapeutic demand for immunoglobulin.

PURPOSE: Estimating the underlying demand for immunoglobulin (Ig) is important to ensure that adequate provision is made for patients with primary immune deficiency (PID) in the context of the competing demands for Ig and to ensure optimal therapeutic regimens. The concept of latent therapeutic demand (LTD) was used to estimate evidence-based requirements and compared to the actual Ig consumption in different countries. The estimates were performed for common variable immunodeficiency (CVID) and X-linked Agammaglobulinaemia (XLA), the two most commonly studied PIDs using Ig. METHODS: The LTD model for CVID and XLA was derived using decision analysis methodology. Data for the epidemiology and treatment variables were obtained from peer-reviewed publications, clinical registries and publicly-available patient surveys. Incomplete data records from registries were excluded from analysis. The variables impacting LTD were ranked in order of sensitivity through a tornado diagram. The uncertainty surrounding the variables was modeled using probabilistic distributions and evaluated using Monte Carlo simulation. RESULTS: Treatment dosage and prevalence were determined to be the most sensitive variables driving demand. The average potential usage of Ig for the treatment of CVID and XLA was estimated at 72 g per 1,000 population, which is higher than the estimated Ig usage in CVID and XLA of 27-41 g per 1,000 population in the US. CONCLUSION: The potential demand for treating CVID and XLA exceeds the currently observed usage of Ig in these disorders. Variable usage in different countries is due to varying prevalence and dosage practices. Under-reporting in patient registries represents a major obstacle to calculating the true prevalence of CVID and XLA. Modeling demand relies heavily upon accurate prevalence and practice estimates which reemphasize the importance of accurate registries and improved registry methods. As better data becomes available, revision of model variables provides opportunities to anticipate and prepare for evolving patient needs.

Economic evaluation of immunoglobulin replacement in patients with primary antibody deficiencies.

Lifelong immunoglobulin replacement is the standard, expensive therapy for severe primary antibody deficiencies. This treatment can be administrated either by intravenous immunoglobulin (IVIG) or subcutaneous infusions (SCIG) and delivered at home or in an out-patient setting. This study aims to determine whether SCIG is cost-effective compared with IVIG from a French social insurance perspective. Because both methods of administration provide similar efficacies, a cost-minimization analysis was performed. First, costs were calculated through a simulation testing different hypothesis on costs drivers. Secondly, costs were estimated on the basis of field data collected by a questionnaire completed by a population of patients suffering from agammaglobulinaemia and hyper-immunoglobulin (Ig)M syndrome. Patients' satisfaction was also documented. Results of the simulation showed that direct medical costs ranged from 19 484 euro for home-based IVIG to 25 583 euro for hospital-based IVIG, with home-based SCIG in between at 24 952 euro per year. Estimations made from field data were found to be different, with significantly higher costs for IVIG. This result was explained mainly by a higher immunoglobulin mean dose prescribed for IVIG. While the theoretical model showed very little difference between SCIG and hospital-based IVIG costs, SCIG appears to be 25% less expensive with field data because of lower doses used in SCIG patients. The reality of the dose difference between both routes of administration needs to be confirmed by further and more specific studies.

Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century.

OBJECTIVES: To provide a review of the world literature and discuss the clinical role of subcutaneous immunoglobulin (SCIG) therapy for primary antibody deficiency. DATA SOURCES: English-language publications on SCIG therapy were identified through MEDLINE and through the reference list of the initially identified publications. STUDY SELECTION: Articles pertaining to SCIG for the treatment of immunodeficiency, particularly primary antibody deficiency, were selected. RESULTS: SCIG therapy has been shown to be effective and safe for the treatment of primary immunodeficiency. The risk of systemic reactions during infusion is generally reported to be less than 1%. Many patients prefer SCIG over conventional intravenous immunoglobulin therapy because of increased convenience and independence associated with SCIG therapy. Publications show SCIG therapy to be advantageous in selected patient populations, such as children, pregnant women, and patients with poor intravenous access. CONCLUSION: SCIG therapy has been widely used in some European countries for a number of years, but a Food and Drug Administration-approved product was only recently introduced into the United States in 2006. SCIG therapy offers unique advantages that are applicable to many patients receiving immunoglobulin therapy for primary immunodeficiency.

Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs.

Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US $10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.

Selective IgM deficiency: functional assessment of peripheral blood lymphocytes in vitro.

The functional aspects of the peripheral blood lymphocytes from 6 patients with primary selective IgM deficiency (sIgMD) were analyzed to elucidate its pathogenesis. The surface IgM positive B cells were present at almost the same percentage as in controls, but the percentage of cluster of differentiation (CD)4+ T cells was higher and that of CD8+ T cells was low. The patient B cells showed a significantly lower proliferative response to Staphylococcus aureus Cowan strain I (SAC) than control B cells and did not produce a significant amount of IgM when co-cultured with control T cells. Interestingly, mitomycin C (MMC)-treated patient T cells induced a greater amount of IgM production by control B cells. In addition, patient B cells treated with SAC and B cell differentiation factors (BCDF) failed to secrete IgM. These results suggest that the pathogenesis of sIgMD may be mainly due to an intrinsic defect in B cell maturation.

Intravenous immune globulin therapy in hypogammaglobulinemia. A review.

An immune globulin preparation specifically modified for intravenous administration has been employed therapeutically in 30 patients with primary immunodeficiency disease. Our results of this long-term study are summarized within three major categories: (1) Levels of serum IgG produced and maintained after intravenously administered serum immune globulin infusions of 100 to 500 mg/kilo. The disappearance pattern of infused IgG is outlined and individual patient variations emphasized. (2) The therapeutic effects of intravenously administered serum immune globulin therapy are reported and related to dosages of intravenously administered serum immune globulin administered and serum levels of IgG maintained. (3) The incidence and nature of detrimental side effects are outlined, and methods to reduce this problem are indicated. It is recommended that patients with primary immunodeficiency be given from 150 to 200 mg/kilo intravenously administered serum immune globulin, every four weeks, as prophylactic therapy to reduce acute infectious complications. A method to establish an optimum therapy for a specific patient is presented.