Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy

Transfusion Medicine Reviews xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Transfusion Medicine Reviews journal homepage: www.tmreviews.com

Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy Tanja M. Windegger a,⁎, Christine A. Lambooy a,b, Leanne Hollis a,c, Karen Morwood d, Helen Weston b, Yoke Lin Fung a,e a

School of Health and Sport Sciences, University of the Sunshine Coast, Queensland, Australia Department of Cancer Care Service, Sunshine Coast, Hospital and Health Service,Queensland, Australia Safety, Quality and Innovation Unit, Sunshine Coast, Hospital and Health Service, Queensland, Australia d Department of Immunology, Sunshine Coast, Hospital and Health Service, Queensland, Australia e Department of Anaesthetics, Sunshine Coast, Hospital and Health Service, Queensland, Australia b c

a r t i c l e

i n f o

Available online xxxx Keywords: Secondary hypogammaglobulinemia Immunoglobulin replacement therapy SCIg Efficacy HRQoL Health economics

a b s t r a c t Immunoglobulin replacement therapy (IRT) has an important role in minimizing infections and improving the healthrelated quality of life (HRQoL) in patients with immunodeficiency, who would otherwise experience recurrent infections. These plasma-derived products are available as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). The global demand for these products is growing rapidly and has placed pressure on supply. Some malignancies and their treatment (as well as other medical therapies) can lead to secondary hypogammaglobulinemia or secondary immunodeficiency (SID) requiring IRT. Although IVIg use in this cohort has well-established therapeutic benefits, little is known about SCIg use. A literature search in July 2015 found only 7 published articles on SCIg use. These articles found that both IRT modes had equivalent efficacy in regard to reduction of bacterial infections. In addition, SCIg was reported to produce higher serum IgG trough levels compared with IVIg on equivalent dosage with the added benefit of fewer adverse effects. Patient HRQoL reports demonstrate preference for SCIg because of reduced adverse effects and hospital visits. There are no health economic models published on SCIg use in SID, but models on primary immunodeficiency disease and IRT conclude that SCIg provided greater economic benefits than IVIg. The findings of this small number of reports suggest that SCIg therapy for patients with SID is likely to be beneficial for both the patient and health care providers. To substantiate wider use of SCIg in SID, larger and more detailed studies are needed to accurately quantify the effectiveness of SCIg. © 2016 Elsevier Inc. All rights reserved.

Contents Strategies for Literature Search . . . . . . . . . . Clinical Outcome . . . . . . . . . . . . . . . . . Serum IgG Levels. . . . . . . . . . . . Infection Rates and Antibiotic Use . . . . Dosage . . . . . . . . . . . . . . . . Adverse Events and Side Effects of SCIg. Health-Related Quality of Life . . . . . . . . . . Health Economics . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . Conflict of Interest. . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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Funding: TM Windegger was supported by grants from the National Blood Authority Australia and Wishlist, Sunshine Coast Health Foundation. ⁎ Corresponding author at: Tanja M. Windegger, School of Health and Sport Science, University of the Sunshine Coast, Queensland, Australia E-mail address: [email protected] (T.M. Windegger).

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Immunoglobulin (Ig) products have been administrated intravenously as replacement therapy to treat immunodeficiency since the 1980s [1-3]. Ig products are also used as immunomodulatory agents in autoimmune disease, but this will not be covered in this review. Both

http://dx.doi.org/10.1016/j.tmrv.2016.06.006 0887-7963/© 2016 Elsevier Inc. All rights reserved.

Please cite this article as: Windegger TM, et al, Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy, Transfus Med Rev (2016), http://dx.doi.org/10.1016/j.tmrv.2016.06.006

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T.M. Windegger et al. / Transfusion Medicine Reviews xxx (2016) xxx–xxx

primary immunodeficiency (PID) and secondary immunodeficiency (SID) compromise an individual's ability to produce functional immunoglobulins and thus diminish their resistance to infection. Ig products contain the spectrum of affinity-matured IgG derived from a large pool of healthy blood donors, which have immunological functions of neutralization, opsonization, sensitization, and activation of the complement system [4-6]. Although the mechanisms for the therapeutic effects of Ig products are not completely understood, the presence of F(ab’) fragments in the product provides antigen recognition function, whereas the Fc fragments enable activation of immunity [7]. Readers are referred to a recent review of mechanisms of actions of Ig preparations by Matucci et al [7]. Patients with recurrent infections are considered for immunoglobulin replacement therapy (IRT) regardless of their serum IgG levels. However, the level of serum IgG which defines immunodeficiency varies with the patient's age, underlying disease, and clinical status. In lung transplant patients, IgG levels of 4.0-6.9 g/L are considered as mild immunodeficiency, and levels less than 4 g/L are considered severe immunodeficiency [3]. Pediatric hemopoietic stem cell transplant (HST) patients are considered immunodeficient when their serum IgG level falls below 4 g/L [8]. The IgG level used to define immunodeficiency in SID varies, as some studies use IgG levels of less than 5 g/L [9] and others levels of less than 5.5 g/L [10]. Nevertheless, IRT is warranted in patients with recurrent infections regardless of severity of the underlying immunodeficiency disease [3,9]. Both PID and SID can be treated by administration of Ig, either as intravenous immunoglobulin (IVIg) or subcutaneous immunoglobulin (SCIg). Although much is known about IVIg and SCIg therapy for PID patients, the same cannot be said for SID. This literature review will focus on SID patients using SCIg replacement therapy. The terms acquired hypogammaglobulinemia and secondary immunodeficiency are used interchangeably in this review and abbreviated to SID. Hypogammaglobulinemia can be secondary to malignancies that affect immunoglobulin production, such as chronic lymphocytic leukemia (CLL) [9,11-14], multiple myeloma, B-cell lymphoma, primary amyloidosis, and monoclonal gammopathy of unknown significance [5,6,9,10]. Between 27% and 52% of patients with CLL are diagnosed with hypogammaglobulinemia [9,13], and depending on the stage of the disease, this can be as high as 85% of patients [11]. This places these patients at risk of developing infections, thus influencing their morbidity and mortality. Estimates indicate that 25%-50% of deaths in patients with CLL are due to infection [12,15]. However, one study reported that all their CLL patients had the same risk of infection (79%) regardless of their serum IgG levels [13]. Other mechanisms that influence the susceptibility to infection in CLL patients include lymphocyte dysfunction, neutropenia, and a defective complement system [12]. Immunodeficiency can also be secondary to treatment of the patient's underlying disease [10]. Up to 6.6% of patients treated with rituximab develop symptomatic hypogammaglobulinemia [10,16], with 38.5% experiencing transient hypogammaglobulinemia [9], with subsequent increased risk of infection [14,16,17]. Treatment with glucocorticoids [10,18] has been reported to cause decreased serum IgG levels in 12% of patients [9], and anticonvulsant therapy has also been associated with the development of antibody deficiency [10,18]. The immunosuppressive treatments received by recipients of solid organ transplants are estimated to cause hypogammaglobulinemia in 14%-37% of patients [3,18,19]. Similarly, more than a third of children who received a lung transplant developed prolonged hypogammaglobulinemia [8]. Some treatment-related hypogammaglobulinemias are short lived, whereas others can be long term. Viral infections, including human immunodeficiency virus, EpsteinBarr virus, cytomegalovirus, and parvovirus B19, have also been associated with antibody deficiency that can increase susceptibility to infections [9,18]. As multiple factors may contribute to reduced serum IgG levels (ie, malignancy, treatment regimens, renal dysfunction [10,18], and/or

viral infections), SID patients are a heterogeneous group. Because of their complex clinical presentation, it is often impossible to establish the exact cause of the hypogammaglobulinemia. Hence, it is not always clear if IRT will be of benefit to these patients. In recent years, some countries have developed guidelines for the appropriate use of IRT [20-22], although clinical classifications used are not consistent. The efficacy of IVIg replacement therapy for SID has been well documented, and there are clear guidelines on its use in hematological conditions [15,20,23,24]. Total IgG product use for SID patients is variably estimated at 35% in Canada [25] and 21% in Australia [26]. In the United Kingdom, 11% are hematology patients and 7% are hemato-oncology patients [27]. There are presently no specific guidelines or recommendations for SCIg use and only a very small number of published reports on the efficacy of SCIg programs in SID patients. This article begins to address this knowledge gap with a literature search on the use of SCIg in SID patients. Strategies for Literature Search A systematic literature search of the following databases: PubMed, Google Scholar, Web of Science, ProQuest Health & Medical Complete, Annual Review, Scopus, Informit, EBSCO, and Cochrane Library, was conducted on 24 June 2015 for studies related to SID patients treated with SCIg replacement therapy (Fig 1). The keywords used were acquired hypogammaglobulinemia, secondary immunodeficiency, subcutaneous, SCIg, and malignancy (Fig 1). Broad keywords were chosen to minimize risk of missing studies that used mixed cohorts and included patients with SID. Any studies that were on IVIg use only, literature reviews, meta-analyses, abstracts, meeting reports, and books were excluded. For the remaining studies, the title, abstract, and methods section were screened to assess relevance. The search was completed without further restriction and identified 7 articles that included SID patients treated with SCIg replacement therapy, which are summarized in Table 1. The study cohorts in the 7 articles varied and included patients with CLL, non-Hodgkin lymphoma, HST, and lung transplant recipients (Table 1). There was significant variation in the age of patients. One study had a pediatric cohort [8], another covered an age range from 1 to 74 years [28], 3 studies had a cohort mean age between 60 and 70 years [3,14,29], and 1 did not indicate the age of patients [30]. The Canadian study [25] had no patients, as it was based on a population estimate and reported only on economic benefits from switching PID and SID patients from IVIg to SCIg. Two studies, the Swedish study by Hammarström et al [30] and the American study by Koterba and Stein [29], only included patients who commenced on SCIg and were naive to prior Ig therapy, whereas 3 studies, Compagno et al [14], Hoffmann et al [28], and Shankar et al [3], also reported on patients who started with IVIg and subsequently switched to SCIg. In the pediatric study [8], they compared HST patients who continued with IVIg therapy with those who switched to SCIg. It is worth noting that the cohort numbers of all the studies were small, with the largest study cohort containing 61 patients split into 2 groups [14] (Table 1). Clinical Outcome Serum IgG Levels Although IgG levels greater than 6 g/L are considered normal for adults, there appears to be no consensus on the serum IgG level which provides protection from infection. In SID patients, this is further complicated by the heterogeneity of their underlying disease. Six studies (total n = 111 patients) included data on serum IgG trough levels in patients with SID (Table 1). In the earliest report, SID patients, who received SCIg therapy at a dose of 50 mg/kg/wk, demonstrated an increase of serum IgG levels from 3.1 to 5.5 g/L posttherapy [30].

Please cite this article as: Windegger TM, et al, Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy, Transfus Med Rev (2016), http://dx.doi.org/10.1016/j.tmrv.2016.06.006

T.M. Windegger et al. / Transfusion Medicine Reviews xxx (2016) xxx–xxx

3

Fig 1. Summary of literature search strategy conducted on the 24 July 2015 on SCIg therapy in patients with SID.

Four studies reported that the mean serum IgG trough level was higher with SCIg therapy compared with IVIg therapy [3,8,14,28]. Interestingly, in 2 studies, patients who switched from IVIg to SCIg achieved a significant (P b .05 [14], P b .01 [28]) increase in serum IgG levels even with no change in dosage (Table 2). The available data demonstrate that both modes of therapy can successfully elevate serum IgG levels in SID patients. Infection Rates and Antibiotic Use The primary goal of IRT is to reduce infection rate and antibiotic use. There were 3 reports on infection rate in SID patients treated with SCIg therapy (total n = 90) [8,14,30], but only 2 included information on antibiotic use (total n = 78) (Table 1) [14,30]. The earliest study was performed in Sweden and was a retrospective study comparing patient's hospital admission due to infection and antibiotic use before IRT with SCIg treatment in 17 SID patients [30]. Although SCIg replacement therapy increased patient IgG levels, the levels were still less than the reference range (5.5 g/L). In spite of this, they recorded a decrease in antibiotic use, as well as a decrease in hospital admission due to infection (Table 1) (P b .05 Wilcoxon signed rank) [30]. Although the cohort was small, it provided important early evidence that SCIg administration did reduce the number of severe infections in SID patients. A recent pediatric HST cohort study reported similar mean numbers of infection (bacterial, viral, fungal, or unidentified) in both IVIg (n = 46) and SCIg (n = 12) users [8]. However, there was no apparent statistical analysis of the data to explain the significance of the conclusion. The third was a retrospective Italian study of 61 SID patients who switched from IVIg to SCIg [14]. It reported a reduction in infection

rate and use of antibiotics when the patients were on SCIg, even though they maintained a dosage equivalent to their previous IVIg treatment [14]. When the patients were on IVIg, they were reviewed monthly, but when on SCIg, they were only reviewed every 3 months. Whether this variation in monitoring contributed to lower infection rates in the SCIg period was not discussed. Details on annual infection rate and cycles of antibiotic use per patient year were collected, but there was no apparent statistical analysis to demonstrate significance. In spite of their limitations, these 3 studies consistently record that SCIg use in SID is associated with reduced antibiotic use and infection. But larger studies with statistical analysis are required to confirm this association. What also needs to be investigated is whether the stage of hematological malignancy of a patient affects efficacy of IRT. Dosage There appears to be no consensus on the optimum target serum IgG levels or the therapeutic dosage of Ig products for patients with SID. It is unclear if the Ig dose should be changed or maintained when switching from IVIg to SCIg [2,19]. One study of 37 patients [31] reported no change in infection rate in PID patients, who changed from IVIg to SCIg, along with a dosage reduction (from 817 mg/kg/month IVIg to a lower SCIg dose of 675 mg/kg/month). In contrast, some countries add a dosing coefficient of 137% when switching PID patients from IVIg to SCIg [32,33]. The published data for SID patients covers a broad range in SCIg dosage: from 50 to 200 mg/kg/wk (Table 1). More recent studies indicate a preference for determining each patient's “biological IgG level,” i.e. the level at which an individual is free of serious infections, rather than using the reference range adjusted for sex and age [34] or “per kg of

Table 1 Summary of 7 peer-reviewed publications on patients with SID using SCIg replacement therapy Author

Cohort

SCIg Switched IVIg to IVIg only (n) SCIg dose Average serum Change in Change in only (n) SCIg (n) (mg/kg/wk) Ig level (g/L) infection rate antibiotic use

Hammarström et al, 1995 (Sweden) [30] Sundin et al, 2012 (Sweden) [8] Shankar et al, 2013 (US) [3] Compagno et al, 2014(Italy) [14]

SID malignancy PAE HST Lung transplant recipient SID (B-CLL, NHL)

17 0 3 28

Studies with results from mixed cohorts PID and SID Hoffman et al, 2010 (Germany) [28] PID/SID Koterba and Stein, 2014 (US) [29] PID/SID (NHL) Gerth et al, 2014 (Canada) [25] PID/SID

0 12 7 33

0 46 0 0

50 100-200 100 75

5.5 N4.0 8.9 6.6

Decreased Equivalent N/A Decreased

4 5 0 91 7.5 N/A 2 0 0 100 9.4 N/A Population estimate to analyze economic benefit from a switch of IVIg → SCIg

Decreased N/A N/A Decreased

N/A N/A

PAE HST, pediatric hemopoietic stem cell transplant; N/A, no data available; B-CLL, B-cell chronic lymphocytic leukemia; NHL, non-Hodgkin lymphoma.

Please cite this article as: Windegger TM, et al, Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy, Transfus Med Rev (2016), http://dx.doi.org/10.1016/j.tmrv.2016.06.006

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T.M. Windegger et al. / Transfusion Medicine Reviews xxx (2016) xxx–xxx

Table 2 Summary of mean Ig dosage and serum Ig trough levels achieved with IVIg and SCIg replacement therapy in patients with SID Reference

Equivalent mean weekly dosage (mg/kg/wk)

Baseline

Serum Ig trough levels with IVIg therapy (g/L)

Serum Ig trough levels with SCIg therapy (g/L)

Hoffman et al, 2010 [28] Compagno et al, 2014 [14]

91 75

N/A 3.8

6.6 4.7

7.5 6.6

bodyweight” [35]. It is worth mentioning that the lowest reported dosage of 50 mg/kg/wk was associated with a decrease in infection rate [30]. This raises the question: Can SID patients remain infection free on a lower dose of SCIg than PID patients because of different underlying disease mechanisms and other patient factors? Adverse Events and Side Effects of SCIg The most common reported adverse effects were swelling, erythema, pain, and discomfort at infusion sites [3,8,14,28,30]. There were no reports of severe adverse events. Data on the incidence of adverse effects in patients who switched from IVIg to SCIg therapy come from 4 studies, involving 92 SID patients in total (Table 1) [3,8,28,30]. Patients with renal dysfunction were no worse off on SCIg replacement therapy compared with IVIg [3]. In the study of Compagno et al [14], only 1 of 61 patients (2%) required premedication and received nonsteroid antiinflammatory drugs before SCIg infusion compared with 17 of 33 patients (52%) on IVIg. There were also fewer cutaneous reactions with SCIg in SID patients compared with PID patients, possibly because of difference in the underlying disease [14]. Infusion-related headaches (a common adverse effect of IVIg) resolved once patients switched from IVIg to SCIg [8]. The limited data available indicate equal efficacy of the 2 modes of therapy and an increase in serum IgG trough levels when patients switch from IVIg to SCIg on the equivalent monthly dosage. The absence of adverse events and severe side effects makes SCIg an attractive alternative for patients with SID. However, these small and mixed cohorts make it difficult to draw clear conclusions. Further studies are also required to determine if SID patients can remain infection free on a lower SCIg dose compared with IVIg dose. Health-Related Quality of Life Illness and associated therapeutic interventions can affect patient's health-related quality of life (HRQoL). There are a number of validated instruments available to measure the impact on an individual's quality of life, such as the Short Form 36 (SF-36) (http://www.sf-36.org/tools/ sf36.shtml), the European EQ-5D (http://www.euroqol.org/about-eq5d.html), and the Child Health Questionnaire–Parental Form 50 (https://www.healthactchq.com/chq.php). Studies in PID patients have reported improved HRQoL when switching from IVIg to SCIg therapy [36-39], with most PID patients indicating a preference for SCIg therapy. Reasons provided include fewer infusion-related adverse events such as prolonged headaches [40], more independence [38], and the greater flexibility of home administration [41]. This search only found 3 HRQoL studies in SID patients. The 2 questionnairebased HRQoL reports (total n = 50) documented a similar positive experience [14,28]. A mixed cohort study with 48 PID and 5 SID patients used the SF-36 [28]. The results demonstrated significant improvement in the categories of bodily pain, general health perceptions, and vitality when comparing baseline data with follow-up data at 9 months. For the younger PID/SID patients (b14 years old), the Child Health Questionnaire– Parental Form 50 was completed by the parent or guardian. The results showed significantly improved scores for the General Health Perception, Parental Impact–Emotional, Parental Impact–Time, and Family

Activities Scales [28]. In addition, SCIg therapy was considered more flexible by 86% of patients when compared with IVIg [28]. It was not possible to determine if positive results on HRQoL from mixed cohorts would remain true if only patients with SID were analysed. Another study of 33 patients used a modified version of SF-36 and reported an overall improvement in HRQoL when SID patients were switched from IVIg to SCIg therapy [14]. In that study, improvements were mainly attributed to the elimination of adverse events, decrease in infectious events, and convenience of home therapy [14]. In the third study, parents of the children who received SCIg following HST participated in a semistructured interview conducted by nurses to evaluate attitudes to IRT, frequency and duration of therapy, and preference of mode of therapy [8]. Although not requiring venous access was seen as a benefit, the reduction of clinic visits associated with SCIg was the major reason given for choosing SCIg over IVIg [8]. Overall, the positive impact reported on HRQoL for SID patients raises the question of why home-based SCIg programs are not more widely used. Health Economics The rapidly growing cost of health care naturally raises the question of whether switching patients on IVIg to SCIg therapy might provide savings for the health care budget. A systematic review of PID and CLL patients using IRT between 1982 and 1996 highlighted the absence of high-quality economic studies [42]. This literature search found only 3 reports that calculated costs from actual field data for PID patients using SCIg, and there were no reports on SID patients. The 2009 French study included a PID cohort of 36 patients [31], and the 2013 Canadian study included a pediatric PID cohort of 25 patients [43]. The earliest report from Sweden also had a PID cohort but compared the patientborne cost of hospital-based SCIg with home-based SCIg therapy in 30 adult patients [44]. The 2 studies comparing IVIg and SCIg therapy in PID highlighted that the Ig product itself made up the largest portion of overall cost, estimated at 48%-90% of total mean cost [31,43]. The French study reported a lower mean monthly SCIg dose of 23.4 g compared with an average IVIg dose of 32.9 g. This equated to a cost reduction of €5768 per year [31] (Table 3). Interestingly, both PID cohorts had similar mean serum IgG trough levels [31]. In Canada, the total cost of IRT was significantly higher for IVIg (Can$23 845) vs SCIg (Can$19 044) [43] despite patients being on equal Ig dosage (Table 3). This indicates that other variables contribute to and need to be considered when calculating therapy cost. The number of infusion pumps used by patients was identified as another large determinant of cost differences. Despite the use of 2 infusion pumps per patient in a French study (leading to a yearly cost of €7354 for pumps), the total SCIg therapy cost was less compared with IVIg [31]. In contrast, a different French study reported the SCIg cost for PID patients to be higher, as it included the cost of renting electric pumps and furniture for SCIg administration [45]. In the Swedish study, home therapy used only 1 infusion pump to minimize cost to patient, whereas 2 were used for hospital-based SCIg administration [44]. Despite the cost of pumps in Sweden, the overall cost to PID patients on SCIg was lower [44]. Similarly, the Canadian study reported a higher cost of pump and infusion material for SCIg compared with IVIg, but overall cost of SCIg therapy was less [43]. In Canada, the cost of SCIg infusion pumps is met by the patient, whereas IVIg infusion material is covered by the hospital [43]. In contrast, in Australia, the cost of SCIg and IVIg pumps and infusion material is generally met by the health care provider rather than the patient [26]. Thus, responsibility for cost of infusion pumps and material varies between countries [31,43]. The available data indicate that despite the initial cost of purchasing the infusion pump and the training sessions provided, SCIg in PID is the more cost-effective mode of therapy for the health care provider. Another approach in the investigation of the economic impact of IRT is the application of health economic models. Cost-minimization

Please cite this article as: Windegger TM, et al, Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy, Transfus Med Rev (2016), http://dx.doi.org/10.1016/j.tmrv.2016.06.006

T.M. Windegger et al. / Transfusion Medicine Reviews xxx (2016) xxx–xxx Table 3 Summary of yearly cost of Ig therapy from a French and Canadian report on patients with PID Total therapy cost

Ig product cost

Reference

Currency

IVIg

SCIg

IVIg

SCIg

Beaute et al, 2009 (n = 36) [31] Ducruet et al, 2013 (n = 25) [43]

Euro Can$

26 529 23 845

20 289 19 044

18 703 13 084

12 935 12 556

analysis and budget impact models exist for Canada [25,46], Italy [47], Germany [48], and France [31,45], which all indicate savings in favor of SCIg therapy. Cost-minimization analysis is usually applied for comparison of therapy programs with equal efficacy. Given that existing data suggest that SCIg results in elevated serum IgG trough levels, reduced side effects and adverse events, and improved HRQoL, a costeffectiveness analysis appears to be the more suitable model for assessment. Hence, further studies are required to establish cost-effectiveness of both IRT modes in SID patients. The 2 Canadian models indicate that the key economic benefit of SCIg over IVIg therapy is derived from reductions in health care staff time [25,46], producing estimated reductions of Can$5735 per PID patient over a 3-year period [46]. This was because SCIg therapy required 12 hours of nurse time in the first year due to training sessions, then only 6 hours per year thereafter. In contrast, IVIg administration required 57 hours per year ongoing [25]. Using Canadian population estimates, the study predicted that switching 50% of PID/SID patients to SCIg could generate savings of Can$23.3 million in labor costs and reduce the burden of nurse shortages [25]. A German study estimated that their statutory health insurance could save €1777 million per year by switching 60% of PID patients to SCIg [48]. This is due to the marked difference in Ig product cost used for their calculations (€84/g IVIg and €38/g SCIg) [48]. The available published data demonstrate that each country distributes the IRT-associated costs differently. In spite of this, present data suggest that switching PID patients from IVIg to SCIg could potentially generate savings for the health care sector. In summary, the data on SID patients who have switched from IVIg to SCIg demonstrate clinical, HRQoL, and economic benefits. Presently, there are 2 promising larger-scale studies being conducted in Europe, which may address some of these knowledge gaps. In 2011, the EPICURE study [49] based in France commenced. It is an observational, prospective, longitudinal study with the goal of describing the clinical profile of SID patients compared to other treatment modes. The only published data on this study are an abstract on data from 130 patients with no detailed analysis [49]. The SIGNS study (Assessment of Immunoglobulins in a Long-Term Non-Interventional Study) [50] in Germany is a noninterventional, prospective, open-label, cohort study gathering data on Ig product users over 2 years to analyze efficacy, HRQoL, and economic impact. To date, no data from this study has been published.

Conclusion There is a global need to optimize the use of Ig products because it is an expensive product in limited supply with the potential for many more applications. This literature search has identified gaps in knowledge regarding dosage of SCIg in SID patients, its efficacy in infection reduction, and health economic benefits. Based on the small number of retrospective observational studies with relatively small number of SID patients on SCIg therapy, the data thus far indicates that: • the efficacy of SCIg is comparable to IVIg in preventing infection, • serum IgG trough levels for patients with SID are higher with SCIg, • patients on SCIg report improved HRQoL.

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To optimize our use of Ig products and realize the full potential of SCIg for SID, further studies are required to answer the following questions: • Is SCIg effective at reducing infection in SID patients? • Does the stage of underlying hematological malignancy affect the efficacy of IRT in SID patients? • Would switching SID patients from IVIg to SCIg result in a reduction in the quantity of IgG product used? • Should dosage be guided by serum IgG levels or by infection-free response in SID patients? • What is the economic impact of supporting SID patients on SCIg (instead of IVIg) for both the health care sector and patients? Conflict of Interest All authors declare no conflict of interest. Acknowledgment We acknowledge and thank Lisa McKibben for her editorial assistance in preparing this manuscript. References [1] Berger M, Cupps TR, Fauci AS. Immunoglobulin replacement therapy by slow subcutaneous infusion. Ann Intern Med 1980;93(1):55–6. [2] Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, Rezaei N. Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta analysis. J Clin Immunol 2012;32(6):1180–92. [3] Shankar T, Gribowicz J, Crespo M, Silveira FP, Pilewski J, Petrov AA. Subcutaneous IgG replacement therapy is safe and well tolerated in lung transplant recipients. Int Immunopharmacol 2013;15(4):752–5. [4] Janeway C, Travers P, Walport M, Shlomchik M. Immunobiology: the immune system in health and disease. 6th ed. UK: Garland Science Publishing; 2005. [5] Kaveri SV. Intravenous immunoglobulin: exploiting the potential of natural antibodies. Autoimmun Rev 2012;11(11):792–4. [6] Stiehm ER, Keller MA, Vyas GN. Preparation and use of therapeutic antibodies primarily of human origin. Biologicals 2008;36(6):363–74. [7] Matucci A, Maggi E, Vultaggio A. Mechanisms of action of Ig preparations: immunomodulatory and anti-inflammatory effects. Front Immunol 2014;5:690. [8] Sundin M, Nordin K, Jostemyr Y, Winiarski J. Subcutaneous IgG replacement after pediatric SCT. Pediatr Transplant 2012;16(8):866–71. [9] Blot M, Boyer P, Samson M, Audia S, Devilliers H, Leguy V, et al. Should mild hypogammaglobulinemia be managed as severe hypogammaglobulinemia? A study of 389 patients with secondary hypogammaglobulinemia. Eur J Intern Med 2014;25(9):837–42. [10] Duraisingham SS, Buckland M, Dempster J, Lorenzo L, Grigoriadou S, Longhurst HJ. Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement. PLoS One 2014;9(6):e100324. [11] Hamblin AD, Hamblin TJ. The immunodeficiency of chronic lymphocytic leukaemia. Br Med Bull 2008;87:49–62. [12] Ravandi F, O'Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother 2006;55(2):197–209. [13] Svensson T, Hoglund M, Cherif H. Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia. Scand J Infect Dis 2013;45(7):537–42. [14] Compagno N, Cinetto F, Semenzato G, Agostini C. Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients. Haematologica 2014;99(6):1101–6. [15] Dhalla F, Lucas M, Schuh A, Bhole M, Jain R, Patel SY, et al. Antibody deficiency secondary to chronic lymphocytic leukemia: should patients be treated with prophylactic replacement immunoglobulin? J Clin Immunol 2014;34(3):277–82. [16] Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk 2013;13(2):106–11. [17] Aksoy S, Dizdar O, Hayran M, Harputluoglu H. Infectious complications of rituximab in patients with lymphoma during maintenance therapy: a systematic review and meta-analysis. Leuk Lymphoma 2009;50(3):357–65. [18] Duraisingham SS, Buckland MS, Grigoriadou S, Longhurst HJ. Secondary antibody deficiency. Expert Rev Clin Immunol 2014;10(5):583–91. [19] Kerr J, Quinti I, Eibl M, Chapel H, Spath PJ, Sewell WA, et al. Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe. Front Immunol 2014;5:629. [20] Jurisdictional Blood Committee, for and on behalf of the Australian Health Ministers' Conference. Criteria for the clinical use of intravenous immunoglobulin in Australia. 2nd ed. Canberra: Commonwealth of Australia; 2012.

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Please cite this article as: Windegger TM, et al, Subcutaneous Immunoglobulin Therapy for Hypogammaglobulinemia Secondary to Malignancy or Related Drug Therapy, Transfus Med Rev (2016), http://dx.doi.org/10.1016/j.tmrv.2016.06.006