Home-Based Infusion of Alglucosidase Alfa Can Safely be Implemented in Adults with Late-Onset Pompe Disease: Lessons Learned from 18,380 Infusions

All adult patients with LOPD who started treatment with alglucosidase alfa between 1999 and 2018 at the Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands, were included. Infusions with alglucosidase alfa from Chinese hamster ovary (CHO) cells between 2002 and 2019 were included for analysis in this study. We used observational routinely collected infusion data, collected per our standardised protocol. All patients had a confirmed diagnosis of Pompe disease, as demonstrated by a deficiency of alfa-glucosidase (EC 3.2.1.20) in leucocytes, fibroblasts, and/or two disease-causing GAA variants in trans. All patients received their first infusion after the age of 18 years and provided informed consent. They were followed up within a standardised protocol approved by our Institutional Review Board (IRB; METC 2007-103). Twenty patients were initially included in the randomised, double-blind, multicentre, placebo-controlled study on the effects of alglucosidase alfa in late-onset Pompe patients (Late-Onset Treatment Study [LOTS/AGLU02704], NCT00158600) [1] and the subsequent open-label study (AGLU03206, NCT00455195) [15].

Alglucosidase alfa infusions were initially given in the hospital for a year to monitor patients and assess the safety of infusions. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions in the hospital setting and if a home nurse trained by the Erasmus MC was available to administer infusions at home (or at a regional hospital if preferred by the patient). The nurse stays at home for the entire duration of the infusion. The infusion line is then flushed with at least 20 mL NaCl 0.9%, after which the nurse stays with the patient for an additional 15 min, or longer on indication. Logistics for infusions provided in a regional hospital were similar to those in the home situation.

All infusions were prepared centrally at our hospital’s pharmacy and were then transported to the regional pharmacy of the patient under strict conditions with continuous temperature monitoring. A standard operating procedure (SOP) was in place, describing the administration of alglucosidase alfa and the management of IARs and other emergencies (e.g. extravasation). Infusions were administered stepwise according to a standard infusion schedule, 0.2, 0.8, and 3.5 mg/kg/h with steps of 30 min for the first three infusion steps and 10 mg/kg/h for the remainder of the infusion (see Online Resource 6, Table 1). Infusion rates might be adapted if needed to treat or prevent IARs (see Online Resource 6, Table 2 for our slow infusion schedule). Premedication was not given as standard prior to infusion but could be considered after the occurrence of IARs. Patients were monitored in line with the SOP using on-site charts with preset checklists. For each infusion, an infusion form was filled out, containing information on the vital parameters (before, during, and right after infusion), the dosage and volume administered, (pre)medication (if any), applied infusion schedule, start and stop time of the infusion, and possible adverse effects of ERT during infusion (if present). A specialised education programme for home nurses was developed at the Erasmus MC to ensure safe administration of ERT at home, including training by our specialised nurses on how to manage IARs in the home situation. An on-call service from the Erasmus MC run by nurses and doctors with experience with ERT in Pompe disease was available for consultation on questions and emergencies related to alglucosidase alfa administration.

We defined an IAR as a disorder characterised by an adverse reaction related to the infusion of pharmacological or biological substances [16]. Nurses and doctors from our centre with experience treating Pompe disease, and trained homecare nurses, graded the IARs based on the classification described in Online Resource 1. If the severity of the IARs had not been graded, the researchers retrospectively graded the infusions (ID, HvdH, HH) according to the Common Terminology Criteria for Adverse Events (CTCAE) classification version 5.0 to avoid classification bias [16]. CTCAE Grade 1 corresponds with mild, CTCAE Grade 2 with moderate, and CTCAE Grades 3, 4, and 5 correspond with severe in the classification in Online Resource 1 [1]. We defined IARs as a serious adverse event (SAE) when an undesired medical event occurred that was fatal, and/or threatened the life of the subject, and/or made hospital admission or an extension of the admission necessary, and/or caused persistent or significant invalidity or work disability [17]. If an IAR occurred in the home situation, patients received subsequent infusions in the hospital if indicated based on the severity of the IAR (see Fig. 2). Patients were transferred back to the home when hospital infusions were assessed to be safe on a case-by-case basis.

Data on general descriptives (sex, genotype, age at symptom onset, age at diagnosis, age at start of ERT, disease duration at start of ERT from symptom onset, disease duration at start of ERT from diagnosis, duration of ERT) were collected. Based on the data on the infusion forms, the following information was collected: data on infusions (number of infusions in hospital and at home, number of infusions per patient, infusion schedule) and data on IARs (number of IARs, fever prior to infusion, sick/ill prior to infusions, severity of IAR, type of IAR, most severe intervention needed, action taken next infusion, premedication next infusion).

For interventions taken in response to IARs, the most severe intervention needed was reported, with the severity ranging from mild to severe in order: none taken, set infusion back to the previous step, paused infusion and restarted infusion later, antihistamine was given, other medication was given, corticosteroid was given, antihistamine and corticosteroid were given, stopped infusion completely, and the patient required immediate clinical evaluation in hospital. For the action taken the next infusion after an IAR occurred, the most severe intervention needed was reported, with the severity ranging from mild to severe in order: none taken, the patient received premedication, infusion schedule was adapted, and the subsequent infusion was given in hospital. Only IARs clinically judged to have a probable or definite relationship with the infusion were included. To evaluate whether we missed any IARs based on the infusion forms, we checked the adverse event forms that were submitted to the pharmacovigilance department of Sanofi. Three researchers (ID, HvdH, and HH) had access to the database population used to create the study population. Data were cleaned by checking all data in duplicate, checking for missing values, and checking for numerical outliers. This study does not include data linkage across databases.

Statistical analysis was executed using SPSS 25.0 (IBM Corporation, Armonk, NY, USA). Data were cleaned by checking for outliers. Descriptive analyses were performed, tabulating demographic and clinical information of patients, an overview of administered infusions, types of IARs, and actions taken to resolve these. Descriptive data (numbers, median, ranges, and percentages) were reported. We did not perform any statistical tests. If data were missing, it was reported as such.

A total of 121 adult Pompe patients treated with alglucosidase alfa in The Netherlands were included in this study. All adult Pompe patients who met the inclusion criteria and for whom data were available were included. We did not filter participants based on data quality or linkage. Of these 121 patients, 95 (78.5%) received home infusions at some point. In February 2019 (data cap of the study), 85 of the 121 patients (70.2%) were receiving treatment with ERT (71 [58.7%] at home, 9 [7.4%] at a regional hospital, and 5 [4.1%] in the Erasmus MC). Reasons for receiving infusions at the Erasmus MC other than starting treatment with ERT were IARs, comorbidities, or a patient preference to receive their infusions at the Erasmus MC. Thirty-six patients were not receiving treatment with ERT as of February 2019. Twenty patients died while receiving treatment. ERT was stopped in 16 patients; 8 of these patients were alive at study end and 8 patients had passed away. The reasons to abort treatment are discussed later. In total, 28 patients (23.1%) had passed away due to respiratory problems (n = 8, 28.6% of deaths), malignancy (n = 6, 21.4%), cardiovascular problems (n = 3, 10.7%), cardiorespiratory failure (n = 2, 7.1%), an infection (n = 2, 7.1%), respiratory insufficiency and decubitus (n = 1, 3.6%), aortic dissection (n = 1, 3.6%), an infection and cardiovascular problems (n = 1, 3.6%), and an autoimmune disorder (n = 1, 3.6%). In three patients (10.7% of deaths), the cause of death was not recorded. None of the deaths were related to IARs.

Patient characteristics are described in Table 1. The median age at symptom onset was 33.5 years (range 1.4–67.4) and the median age at diagnosis was 42.9 years (range 1.4–72.2). Patient age at the start of treatment ranged from 19.9 to 76.3 years (median 52.2 years). The time between symptom onset and the start of ERT ranged from 0.2 to 55.7 years (median 13.7 years). The time between diagnosis and start of ERT ranged from 0.2 to 31.1 years (median 3.3 years), which was partly explained by the fact that no treatment was available at the time of diagnosis for a proportion of patients. ERT duration per patient ranged from 0.2 to 16.2 years (median 9.4 years). Most patients (n = 117, 96.7%) carried the IVS1 variant (c.-32-13T>G) plus another disease-associated variant in the GAA gene. Only 3.3% of patients (n = 4) carried two disease-associated variants other than IVS1.

Infusion characteristics of 18,380 infusions provided to patients since 2002 are described in Table 2. Of these infusions, 27.0% (n = 4961) were given in hospital and 73.0% (n = 13,419) were given at home. The median number of infusions per patient was 148 (range 6–330). In all but one patient, treatment with ERT was initially started in the hospital (for an overview of when to start home treatment, see Fig. 1). This patient started treatment with ERT in a nursing home due to colonisation by highly resistant microorganisms. During this patient's first infusions, a physician and an additional nurse were present, similar to the situation in the hospital. The median duration until the start of home infusion was 17.4 months (interquartile range [IQR] 12.4–25.8, range 0.0–121.4). This value was partly explained by the fact that some patients experienced IARs during the first year of treatment or because the home treatment only became available in 2008, with a proportion of patients having received treatment several years prior during a trial. At the end of the study, 83.5% of alglucosidase alfa infusions in adults with Pompe disease were provided in the home situation. Of all infusions, 88.4% (n = 16,243) were administered using the standard infusion schedule, and 8.8% were administered using an adapted infusion schedule (Table 2). Ninety-three patients always received infusions as per the standard schedule, and 28 patients received infusions using an adapted infusion schedule at some point during treatment. The median duration for an infusion administered using the standard infusion was 205 min (IQR 195–210, range 125–518), and the median duration of an adapted infusion was 255 min (IQR 240–300, range 140–615).

IARs occurred in 257 (1.4%) of 18,380 infusions, of which 144 occurred in the hospital (2.9% of 4961 hospital infusions) and 113 in the home situation (0.8% of 13,419 home infusions). Most IARs were mild (79.9% of IARs in hospital; 92.0% of home-based IARs) (Table 3). Only five severe IARs were reported, one of which occurred at home (Table 3, Online Resource 5). The most prevalent symptoms were chills, itching, trembling, urticaria, localised exanthema, chest discomfort, and headaches (Table 4). An overview of all reported symptoms is presented in Online Resource 3. The median time between the start of treatment with ERT and the first IAR was 7.6 months (IQR 2.3–28.1). The median time between the start of an infusion and the occurrence of an IAR was 180 min (IQR 105.0–255.0) for IARs that occurred during hospital infusions (n = 107) and 150 min (IQR 117.5–192.5) for IARs that occurred in the home situation (n = 61), typically corresponding to step 4 of the infusion schedule. For the remaining IARs, these data were not available.

In total, 32 patients (26.4%) experienced IARs, of whom 21 (65.6% of patients with IARs) experienced their first IAR during the first year of ERT. Most patients with IARs (n = 22, 68.8%) experienced their first IAR in the hospital. Of these, 18 IARs (81.5%) were mild, 3 IARs (13.6%) were moderate, and 1 IAR (4.5%) was severe. Ten patients (31.3% of patients with IARs) experienced their first IAR at home; 6 of these IARs (60.0%) were mild, and 4 (40.0%) were moderate. Twenty-four patients (75.0% of patients with IARs) experienced repetitive IARs. Only 6 patients (5.0% of the total) experienced more than 10 IARs (Table 4). These patients accounted for 181 (70.4%) of all IARs. At study end, 11 of 24 patients with repetitive IARs (45.8%) were treated at home and 2 (8.3%) were treated in a regional hospital. The remaining 11 patients (45.8%) were not under treatment with alglucosidase alfa at the study end.

During our study, 16 patients (13.2%) had stopped treatment with alglucosidase alfa. Eight of these patients have passed away and eight were still alive at study end. In the eight patients who were still alive at study end, treatment was stopped due to IARs (n = 5), burden of ERT (n = 1) non-compliance with therapy (n = 1), and IARs and high antibody titres (n = 1). In the eight patients who had passed away during the study, treatment was stopped due to IARs (n = 1), being terminally ill (n = 4), poor clinical condition, i.e. fully invasive ventilation-dependent and wheelchair bound (n = 1), no effect of ERT (n = 1), and both the burden of ERT and IARs (n = 1).

In 22.9% (n = 33) of IARs occurring in hospital and 72.6% (n = 82) occurring at home, no intervention was needed (Online Resource 4). In 18.1% (n = 26) of hospital-based IARs, pausing the infusion and restarting it after symptoms subsided without needing medication was sufficient. This was also the most frequent intervention for home-based IARs, with 12.4% (n = 14) of IARs subsiding without needing medication. Administration of antihistamines 8.0% (n = 9) was the second most prevalent intervention at home. In the hospital, the most severe interventions needed were the administration of corticosteroids (5.6%, n = 8), antihistamines (18.1%, n = 26), or both (2.8%, n = 4). In 18.1% (n = 26), other medication (such as a beta-blocker or codeine) was needed. Only 16 (0.3%) of the 4961 hospital infusions and 6 (< 0.1%) of the 13,419 home infusions were not restarted (on the same day) after the IAR occurred. Only one IAR in the home situation, during which atrial fibrillation occurred, required immediate clinical evaluation in the hospital. Premedication was only given to patients who had experienced IARs in the past or had a high risk of developing them (e.g. allergic reactions to medication in medical history). In 18.6% of IARs at home (n = 21 of 113) and 66.0 % of IARs in hospital (n = 95 of 144), the patient received premedication before the infusion during which an IAR occurred. The most common premedication to prevent IARs in the hospital were an antihistamine and a corticosteroid (22.2%, n = 32) or only an antihistamine (20.8%, n = 30). In contrast, an antipyretic was the most common premedication in the home situation, at 12.4% (n = 14). For an overview of our protocol regarding the management of IARs and subsequent infusions, see Fig. 2; for an overview of medication to be administered during an IAR and actions and premedication to be considered for the subsequent infusion(s), see Online Resource 2.

After the occurrence of an IAR, no intervention was needed for the subsequent infusion in 16.0% (n = 23) of hospital and 69.9% (n = 79) of home infusions. Administration of premedication was the most prevalent intervention for the infusion after an IAR had occurred, with premedication administered the next infusion after 56.9% of IARs (n = 82) in the hospital and 18.6% of IARs (n = 21) at home. Adaptation of the infusion schedule was the second most prevalent intervention after 18.1% (n = 26) of the IARs in the hospital and 7.1% (n = 8) of IARs at home. In the hospital, an antihistamine and a corticosteroid (27.1%, n = 39) or an antihistamine alone (20.8%, n = 30) were most commonly prescribed. In contrast, an antipyretic drug (11.5%, n = 13) and an antihistamine (9.7%, n = 11) were the most commonly prescribed premedication after an IAR in the home situation (Online Resource 4).

A total of five severe IARs were reported in three different patients, two of whom had two severe IARs each. The first patient experienced the first severe IAR in the home situation after 9 years of ERT and the second in the hospital immediately after. In this patient, the first severe IAR was also an SAE. Before this severe IAR, the patient had previously experienced 30 mild IARs. A second patient experienced two severe IARs in the hospital; she had experienced two previous IARs, a mild IAR a year ago and a moderate IAR during the infusion prior to the severe IAR. The third patient in whom a severe IAR occurred in the hospital had a history of allergic reactions to other medications and was still in the first year of treatment (see Table 5 and Online Resource 5 for a more detailed overview).