Infusion-associated Reactions Research Articles

Safety and Tolerability of a Shorter Agalsidase Beta Infusion Time in Patients with Classic or Later-Onset Fabry Disease

Background: The multisystem manifestations of Fabry disease can create major challenges in patient care. Although enzyme replacement therapy with recombinant agalsidase beta has demonstrated clinical benefits, the standard fortnightly, multi-hour infusion regimen imposes a substantial burden on patients. Methods: We assessed the safety and feasibility of shortening the agalsidase beta infusion time to 90 min in adult patients with classic or later-onset Fabry disease in the absence of premedication. A total of 39 consecutive adult patients (agalsidase-naïve: n = 7; with significant comorbidities: n = 15) with no recent infusion-associated reactions underwent a total of 85 agalsidase beta infusions in our tertiary reference centre for lysosomal diseases. Each infusion was administered at a constant rate (between 0.78 and 1.17 mg/min, depending on the total dose administered). Results: No adverse events of any type (including discomfort and infusion-associated reactions) were reported during or after infusions. The patients’ vital signs and physical examination remained stable, and patients’ satisfaction was high. Conclusions: Our results suggest that shortening the agalsidase beta infusion time to 90 min is safe and feasible in stably treated adult patients with Fabry disease and no recent infusion-associated reactions.

Home infusion experience in patients with Pompe disease receiving avalglucosidase alfa during three clinical trials

During three previously reported clinical trials of avalglucosidase alfa in patients with Pompe disease, 17 out of 142 participants were considered by the investigators to be appropriate candidates for home infusion. During their respective trials, these participants received a total of 419 avalglucosidase alfa infusions at home under healthcare professional supervision. They were clinically stable with no history of moderate or severe infusion-associated reactions within at least 12 months prior to starting home infusions. As of February 25, 2022, the 15 participants with late-onset Pompe disease (LOPD) had received between 2 and 48 home infusions and the 2 participants with infantile-onset Pompe disease (IOPD) had received 19 and 20 infusions. Adverse events occurred in 8 (53 %) participants with LOPD and neither of the participants with IOPD. Seven participants with LOPD had a total of 15 non-treatment-related, non-serious adverse events. One participant with LOPD experienced infusion-associated reactions of eyelid edema and flushing during the first home infusion; both were non-serious adverse events classified as grade 1 (mild). Home infusion was later resumed for this participant. Among LOPD participants, event rates for home infusions were comparable to those for clinic infusions: overall adverse events (0.028 vs 0.039 participants with events/infusion)and adverse events classified as infusion-associated reactions (0.003 vs. 0.006). No medication errors occurred during home infusion. These data suggest that infusion of avalglucosidase alfa at home is feasible and does not compromise safety for patients who have not experienced an infusion-associated reaction during the preceding 12 months of infusions in a clinical setting. Evaluation of real-world experience with avalglucosidase alfa home infusion in countries where it is already approved is ongoing.

Start, switch and stop (triple-S) criteria for enzyme replacement therapy of late-onset Pompe disease: European Pompe Consortium recommendation update 2024.

Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.

#636 A phase 4, open label, multicenter prospective study of the safety and efficacy of agalsidase beta in Chinese patients with Fabry disease

Abstract Background and Aims Fabry disease (FD) is a rare inherited lysosomal storage disease caused by pathogenic GLA gene variants which result in a deficiency of the enzymatic activity of α-galactosidase A. Enzyme replacement therapy (ERT) is the mainstay of FD-specific treatment, but there are currently no reported clinical trials of ERT for FD in the Chinese population. This is the first phase 4 study to evaluate the safety and efficacy of ERT for FD in China since the approval of agalsidase beta in China in 2019. Method A 54-week, phase 4, open label, single arm, prospective, post-marketing surveillance (PMS) study of agalsidase beta (NCT05054387) was performed at 6 sites in China. Twenty-two Chinese ERT-naïve FD participants (≥8 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled and received infusions of agalsidase beta (Fabrazyme®, Sanofi) at a dose of 1.0 mg/kg every 2 weeks for up to 48 weeks. The primary endpoint was safety and tolerability of agalsidase beta. The endpoints of clinical efficacy included the changes of plasma globotriaosylceramide (GL-3), globotriaosylsphingosine (Lyso-GL-3), FD symptoms (including angiokeratoma, hypohidrosis, anhidrosis, abdominal pain, headache, tinnitus, heat tolerance, and activity tolerance), and eGFR from baseline to week 48. A post-hoc subgroup analysis was conducted to explore the differences in ERT efficacy between two subgroups of different ages (<30 years and ≥30 years). Results All 22 patients completed the study intervention. There were 18 males (81.8%) and the mean age of ERT initiation was 29.0 ± 13.5 years. Treatment-related adverse events (AEs) and infusion-associated reactions (IARs) were reported in 8 participants (36.4%), which was less than ∼60% as previously reported for IARs. Most AEs were mild or moderate and no AE caused permanent treatment discontinuation or death. The mean plasma GL-3 and Lyso-GL-3 levels decreased remarkably at week 6 and remained stable throughout the trial, with the mean percentage reduction from baseline to week 6 through week 48 ranged from −34.6% ± 27.4% to ­41.9% ± 14.9% and −58.8% ± 20.2% to ­64.9% ± 12.7%, respectively (Fig. 1a and b). The reduction was more remarkable for the classic male patients (n = 18; GL-3: 7.99 ± 2.19 ug/mL at baseline and 4.31 ± 1.71 ug/mL at week 48, −46.0% ± 18.4%; Lyso-GL-3: 83.11 ± 25.69 ng/mL at baseline and 25.89 ± 13.43 ng/mL at week 48, −67.8% ± 17.6%). Thirteen (59.1%) participants experienced improved FD symptoms at week 48, with no cases of worsening symptoms. The mean eGFR was 115.6 ± 37.3 mL/min/1.73 m2 at baseline and 118.4 ± 42.9 mL/min/1.73 m2 at week 48, with a change of 0.0 ± 12.4 mL/min/1.73 m2 from baseline to week 48 (Fig. 1c). In the subgroup analysis, participants were divided into the younger group with age <30 years (n = 11) and the older group with age ≥30 years (n = 11) according to their age of ERT initiation. At week 48, the reduction of mean plasma GL-3 (−47.1% ± 23.6% vs −22.0% ± 26.0%) and Lyso-GL-3 levels (−72.4 ± 17.3% vs −48.2% ± 19.8%), the stabilization of renal function (the mean change of eGFR from baseline to week 48: 5.2 ± 7.9 mL/min/1.73 m2 vs −5.2 ± 14.1 mL/min/1.73 m2) and the percentage of symptom improvement (81.8% vs. 36.4%) were generally more remarkable in the younger group than in the older group (Table 1). Conclusion This first phase 4 study of ERT for Fabry disease in China demonstrates that agalsidase beta is safe and well tolerated with a relatively low IAR rate, and effective in reducing plasma GL-3 and Lyso-GL-3, improving symptoms, and stabilizing renal function in Chinese patients with FD. Furthermore, the present study implies that patients who initiate ERT at a younger age benefit more from the therapy. Funding: Commercial support - Sanofi Pharmaceuticals.

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in %predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was welltolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

Alemtuzumab infusion-associated reactions and laboratory changes in patients with relapsing-remitting multiple sclerosis at baseline and first-year follow-up

BackgroundAlemtuzumab (ATZ) is an anti-CD52 humanized monoclonal antibody indicated for treating highly active relapsing-remitting MS (RRMS). It alters the regulation of the immune system by depleting circulating lymphocytes. Changes in blood cell count, infusion-related reactions, and changes in vital parameters can be seen in the early period with ATZ. AimChanges in blood tests, serum tests, vital parameters, and characteristics of infusion-associated reactions (IARs) observed during the first course of ATZ treatment and thereafter were evaluated. Materials and methodsThe systolic blood pressure (SBP), diastolic blood pressure (DBP), fever, heart rate (HR), changes in blood and serum tests, and IARs developed after the first course of 23 patients with RRMS who received ATZ treatment were evaluated by comparing the results of 26 patients with RRMS who received only intravenous methylprednisolone. ResultsMean age was 36.60 ± 8.98, 73.9% female (n = 17), diagnosis time was 8.52 ± 3.64 years, pre-EDSS: 3.93 ± 1.80. No significant difference was found in vital parameters except for sub-febrile fever that developed on the first day. The number of white blood cells increased significantly after the first day. The hemoglobin level did not change. Lymphocyte (very high) and platelet (mild) counts decreased starting from the first days, and eosinophil (very high) and monocyte (moderate) counts decreased from the third day. There were no significant changes in liver enzymes, thyroid function tests, serum urea, creatinine, and lipid profile during 1-year follow-up. The IAR rate was 95.6% and occurred most frequently on the second and third days. The most common are dermatological findings (52%), headache (20%), pain (10%) and fatigue (8%). ConclusionAlemtuzumab has no appreciable effect on vital parameters during infusion. However, these changes are not clinically correlated, even if there is. Headache in the first days, dermatological (most common) findings, pain, and fatigue are seen in the following days. Most IARs can be resolved with symptomatic treatment and close follow-up. Lymphocytes, eosinophils, and monocytes are significantly reduced and return to baseline levels towards the end of the first year. The first year does not cause significant pathologies in other serum parameters. However, after the first year, watch out for associated autoimmune pathologies, especially thyroid involvement.

Reducing agalsidase beta infusion time in Fabry patients: low incidence of antibody formation and infusion-associated reactions in an Italian multicenter study

BackgroundFabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated.ResultsTwenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study’s end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved.ConclusionsThe study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.

Real-world outcomes from a series of patients with late onset Pompe disease who switched from alglucosidase alfa to avalglucosidase alfa.

Introduction: Pompe disease is an inherited, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase and accumulation of glycogen in tissues, resulting in cellular dysfunction, muscle damage, and functional disabilities. Enzyme replacement therapy with alglucosidase alfa (Myozyme/Lumizyme) has led to better outcomes, but many patients have plateaued or declined despite treatment. The second-generation ERT avalglucosidase alfa (Nexviazyme) was designed to have enhanced cellular uptake via the conjugation of additional bis-mannose-6-phosphate residues. There have been trials comparing the efficacy of alglucosidase and avalglucosidase, but there remains a need for more real-world data on patients who switched from alglucosidase to avalglucosidase. Methods: A chart review was conducted on n = 15 patients with late-onset Pompe disease followed at a single center who switched from alglucosidase to avalglucosidase and continued for at least 6months. Results: A total of n = 8/15 patients received alglucosidase for more than 3years prior to switching, and n = 7/15 received it for more than 5years prior to switching. There were statistically significant improvements in CK, Hex4, and AST with mean differences of -104.8U/L, -3.0mmol/molCr, and -14.7U/L, respectively, post-switch. 6-Minute Walk Test; comfortable gait speed; Gait, Stairs, Gower, Chair; and Quick Motor Function Test scores improved or stabilized in most patients post-switch (n = 8/12, n = 11/12, n = 9/12, n =7/11, respectively). Of n = 7 patients with pulmonary function testing, n = 4/7 had improved upright FVC. Patient-reported outcomes revealed improvements in dyspnea (n = 4/4), physical function (n = 3/4), fatigue (n = 2/3), and lower back pain (n = 3/3). Avalglucosidase was well tolerated without infusion-associated reactions, and all n = 7 patients on home infusions continued receiving ERT at home. Anti-drug antibodies were seen in n = 9/10 of patients on alglucosidase and n = 8/13 of those on avalglucosidase, with titers below 12,800 in a majority of patients. We also present the first outcome data for a patient with LOPD who is non-ambulatory and a full-time wheelchair user; she demonstrated meaningful improvements in quality of life and motor function with the switch. Discussion: In summary, improved outcomes were seen in most patients, with a subset whose decline persisted. This study presents evidence that switching from alglucosidase to avalglucosidase may be associated with improved outcomes in certain patients with LOPD.

Infusion reactions to adeno-associated virus (AAV)-based gene therapy: Mechanisms, diagnostics, treatment and review of the literature.

The use of adeno-associated virus (AAV)vectors in gene therapy has demonstrated great potential in treating genetic disorders. However, infusion-associated reactions (IARs)pose a significant challenge to the safety and efficacy of AAV-based gene therapy. This review provides a comprehensive summary of the current understanding of IARs to AAV therapy, including their underlying mechanisms, clinical presentation, and treatment options. Toll-like receptor activation and subsequent production of pro-inflammatory cytokines are associated with IARs, stimulating neutralizing antibodies (Nabs) and T-cell responses that interfere with gene therapy. Risk factors for IARs include high titers of pre-existing Nabs, previous exposure to AAV, and specific comorbidities. Clinical presentation ranges from mild flu-like symptoms to severe anaphylaxis and can occur during or after AAV administration. There are no established guidelines for pre- and postadministration tests for AAV therapies, and routine laboratory requests are not standardized. Treatment options include corticosteroids, plasmapheresis, and supportive medications such as antihistamines and acetaminophen, but there is no consensus on the route of administration, dosage, and duration. This review highlights the inadequacy of current treatment regimens for IARs and the need for further research to improve the safety and efficacy of AAV-based gene therapy.

Repurposing of H1-receptor antagonists (levo)cetirizine, (des)loratadine, and fexofenadine as a case study for systematic analysis of trials on clinicaltrials.gov using semi-automated processes with custom-coded software

To gain a comprehensive overview of the landscape of clinical trials for the H1-receptor antagonists (H1R antagonists) cetirizine, levocetirizine, loratadine, desloratadine, and fexofenadine and their potential use cases in drug repurposing (the use of well-known drugs outside the scope of the original medical indication), we analyzed trials from clincialtrials.gov using novel custom-coded software, which itself is also a key emphasis of this paper. To automate data acquisition from clincialtrials.gov via its API, data processing, and storage, we created custom software by leveraging a variety of open-source tools. Data were stored in a relational database and annotated facilitating a specially adapted web application. Through the data analysis, we identified use cases for repurposing and reviewed backgrounds and results in the scientific literature. Even though we found very few trials with published results for repurpose indications, extended literature research revealed some prominent use cases: Cetirizine seems promising in mitigating infusion-associated reactions and is also more effective than placebo in the treatment of androgenetic alopecia. Loratadine may be beneficial in the prophylaxis of G-CSF-related bone pain. In COVID-19, H1R antagonists may be helpful, but placebo-controlled scientific evidence is needed. For asthma, the effect of H1R antagonists only seems to be secondary by alleviating allergy symptoms. Our novel method to find potential use cases for repurposing of H1R antagonists allows for high automation, reduces human error, and was successful in revealing potential areas of interest. The software could be used for similar research questions and analyses in the future.

Safety and tolerability of agalsidase beta infusions shorter than 90 min in patients with Fabry disease: post-hoc analysis of a Japanese post-marketing study

BackgroundAgalsidase beta, an enzyme replacement therapy for Fabry disease, is dosed biweekly at 1 mg/kg body weight, with increasing infusion rates based on tolerability. The US label specifies ≥ 90-min infusions for all patients; the US and EU labels require ≤ 15 mg/hr infusions in patients < 30 kg. The Japanese label allows infusions up to 30 mg/hr, allowing < 90-min dosing for some patients weighing < 45 kg. Japanese post-marketing data were analyzed for rate of infusion-associated reactions (IARs), adverse events (AEs), and serious AEs (SAEs) based on infusion rate and patient attributes (weight, antibody status).ResultsData were available for 436 reduced-duration infusions (< 90 min) and 2242 standard infusions (≥ 90 min). SAEs were rare (0.6%), and the frequency of all safety events decreased over the treatment course. Little impact of infusion duration on safety outcomes was observed: IARs and AEs were numerically more common when infusion duration was ≥ 90 min compared to < 90 min (IARs: 2.0% vs 0.9%; AEs: 2.9% vs 1.4%), while the rate of SAEs was similar (0.4% vs 0.5%). IAR, AE, and SAE frequencies decreased significantly with increasing infusion rates, and this trend was consistent in patients < 30 kg. Safety events tended to be less frequent in patients < 30 kg vs those ≥ 30 kg (IARs: 1.8% vs 2.1%; AEs: 2.3% vs 3.6%; SAEs: 0.0% vs 0.6%), although the differences were not statistically significant. IARs occurred in < 1% of all infusions in the < 30 kg group, 84% of which were < 90 min. More anti-agalsidase beta antibody-positive patients experienced IARs (41.9% vs 30.7%; P = 0.0445) and AEs (61.1% vs 49.3%; P = 0.0497) vs antibody-negative patients; however, there was no significant difference in the frequency of SAEs. In patients with available data, no changes in antibody status were observed after infusion durations were reduced to < 90 min.ConclusionsThe results of this post-hoc analysis demonstrated no significant impact of infusion duration on safety outcomes, and no significant difference in outcomes between patients of different weights. These findings suggest that infusion times in patients who are tolerating treatment can, with careful monitoring, be gradually decreased.

Hypersensitivity infusion-associated reactions induced by enzyme replacement therapy in a cohort of patients with late-onset Pompe disease: An experience from the French Pompe Registry.

Pompe disease is a rare hereditary glycogen storage disorder due to lysosomal acid alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) is the only available treatment. Infusion-associated reactions (IAR) are challenging since there are no guidelines for ERT rechallenge after a drug hypersensitivity reaction (DHR) in Pompe disease. The objective of the present study was to describe IAR and their management in late-onset Pompe disease (LOPD) patients in France, and to discuss the various possibilities of ERT rechallenge. An exhaustive screening of LOPD patients receiving ERT between 2006 and 2020 from the 31-participating hospital-based or reference centers was performed. The patients who had presented at least one hypersensitivity IAR (=DHR) episode were included. Demographic characteristics of the patients, IAR onset and timing, were retrospectively collected from the French Pompe Registry. Fifteen patients among 115 treated LOPD patients in France presented at least 1 IAR; 80.0% were women. Twenty-nine IAR were reported; 18 (62.1%) IAR were Grade I reactions, 10 (34.5%) IAR were Grade II, and 1 (3.4%) IAR was Grade III. IgE-mediated hypersensitivity was found in 2/15 patients (13.3%). The median [IQR] time from ERT introduction to the first IAR was 15.0months [11.0-24.0]. ERT was safely and effectively re-introduced either with premedication alone, or in combination with either modified regimen or desensitization protocol, in all 9 rechallenged patients; including in patients with IgE-mediated hypersensitivity, in the patient with the Grade III reaction, as well as in patients with very high anti-GAA titer. Based on the results herein and previous reports, we discuss premedication and modified regimen for Grade I reactions, and desensitization in Grade II and III reactions. In conclusion, ERT-induced IAR can be safely and effectively managed with a modified regimen or desensitization protocol in LOPD patients.

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

Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present.

Home-based enzyme replacement therapy in children and adults with Pompe disease; a prospective study

BackgroundPompe disease is a lysosomal storage disease treated with life-long enzyme replacement therapy (ERT). Home-based ERT has been provided in the Netherlands since 2008 because it diminishes the burden of treatment, increases patient flexibility and autonomy, and is thus a more patient-centred approach to ERT.MethodsAll Dutch Pompe patients receiving alglucosidase alfa infusions at home were approached to participate in a questionnaire to validate the safety of home-based ERT. Prospective data on symptoms occurring during or within 48 h after infusion and retrospective data on infusion associated reactions (IARs) in the last three months were collected four times during one year.ResultsIn total, 116 out of 120 eligible patients (17 classic infantile, 2 atypical infantile, 15 childhood onset and 82 adult) filled out 423 questionnaires (response rate: 88.1%). Symptoms during or after infusion were reported 27 times in 17 patients. Fatigue was the most commonly reported health complaint (in 9.5% of patients). Four health complaints were judged to be IARs and reported to the Erasmus MC University Medical Center. None of the IARs reported in this study warranted emergency clinical care.ConclusionsOur data demonstrate that home-based ERT in Pompe disease can be safely implemented as few, mostly mild, symptoms were reported during or after infusion. Insights from this study can be used as a base for implementing home-based ERT in other countries and to further optimize patient care, as unreported mild symptoms do not pose a health risk but may still be relevant to the patient.

Olipudase Alfa in Non-CNS Manifestations of Acid Sphingomyelinase Deficiency: A Profile of Its Use.

Olipudase alfa (Xenpozyme™) is an intravenously administered acid sphingomyelinase enzyme replacement therapy indicated to treat non-CNS manifestations of acid sphingomyelinase deficiency (ASMD) in adult and paediatric patients. It is the first and currently the only disease-modifying treatment for ASMD. Olipudase alfa treatment improves hepatosplenomegaly, lung function and platelet counts, along with multiple other pathological features of ASMD in adult and paediatric patients with ASMD. These benefits are sustained through at least 24months of treatment. Olipudase alfa is generally well tolerated; infusion-associated reactions (mostly mild) were the most common treatment-related adverse events. Other warnings and precautions associated with its use include risks of hypersensitivity reactions (including anaphylaxis) and elevated transaminase levels seen in clinical trials, and foetal malformation based on animal studies. All these risks are generally manageable. A gradual dose escalation of olipudase alfa, followed by a maintenance phase, is required to reduce the risks of toxic sphingomyelin catabolites build up, infusion-associated reactions and transient transaminase elevations.

Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults

BackgroundEnzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. Results: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment.ConclusionsOlipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures.NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1.

Enzyme replacement therapy for children with acid sphingomyelinase deficiency in the real world: A single center experience in Taiwan

BackgroundAcid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease with multi-systemic involvement, with no disease-modifying treatment available. Olipudase alfa is an investigational enzyme product developed to replace the deficient acid sphingomyelinase in ASMD patients. Several clinical trials have reported promising safety and efficacy results in adult and pediatric patients. However, no data have been reported outside of the clinical trial setting yet. This study aimed to evaluate major outcomes in pediatric chronic ASMD patients receiving olipudase alfa in the real-world setting. Materials and methodsTwo children with type A/B (chronic neuropathic) ASMD have received olipudase alfa treatment since May 2021. Clinical parameters, including height, weight, complete blood count, liver function tests, lipid profiles, biomarkers, abdominal ultrasonography with shear wave elastography, chest computed tomography, nerve conduction studies, neurodevelopmental evaluations, and six-minute walk tests, were checked at baseline and every three to six months in the first year of enzyme replacement therapy (ERT) to assess its efficacy and safety. ResultsThe two patients in our study started olipudase alfa treatment at the age of 5 years and 8 months and 2 years and 6 months. During the first year of treatment, both patients saw a reduction in their hepatic and splenic volumes as well as liver stiffness. Height z-score, weight z-score, lipid profiles, biomarker levels, interstitial lung disease scores, and bone mineral densities also improved over time. The six-minute walk test showed a gradual increase in walking distance in both patients. There were no obvious improvements or deterioration in neurocognitive function and peripheral nerve conduction velocities after treatment. No severe infusion-associated reactions were noted during the first year of treatment. One patient had two episodes of transient but significantly elevated liver enzymes during the dose-escalation phase. The patient was asymptomatic, and the impaired liver function resolved spontaneously within two weeks. ConclusionOur results provide real-world experience that olipudase alfa is safe and effective in improving major systemic clinical outcomes for pediatric chronic ASMD patients. Monitoring of liver stiffness by shear wave elastography is a noninvasive procedure that can monitor treatment efficacy during ERT.

Efficacy and safety of daratumumab in patients with relapsed/refractory multiple myeloma

Objective: To investigate the efficacy and safety of daratumumab in relapsed/refractory multiple myeloma (RRMM) patients. Methods: Fifty-two RRMM patients treated with daratumumab from September 2019 to November 2021 in West China Hospital were retrospectively enrolled, including 31 males and 21 females. The mean age of these patients at the first diagnosis of multiple myeloma was (58±10) years. According to the dosage of daratumumab, patients were divided into low dosage group (n=10) and high dosage group (n=42). Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse event rates were investigated. Univariate and multivariate analysis of potential factors were conducted. Results: Of the 52 patients, 8 received daratumumab monotherapy, 27 received daratumumab plus immuno-modulatory drug (IMiD) treatment, 4 received daratumumab plus proteosome inhibitor (PI) treatment, and 11 received daratumumab plus dexamethasone treatment. The diagnosis age of high dosage group patients was (57±9) years, which was significantly younger than that of low dosage group [(66±10) years] (P=0.009). The baseline creatinine level of high dosage group patients [M (Q1, Q3)] was 91 (68, 196) μmol/L, which was significantly higher than that of low dosage group [66 (51, 76) μmol/L] (P=0.021). There was no significant difference in other baseline clinical characteristics, previous treatment regimens, previous lines of treatment, and regimen and cycles of daratumumab between the high dosage group and low dosage group (all P>0.05). The ORR for the 52 patients was 71.2% (37/52). The ORR for daratumumab plus IMiD group was 81.5% (22/27), which was significantly higher than that in monotherapy or dexamethasone group [ORR: 52.6% (10/19), P=0.036). With a median follow-up [M (Q1, Q3)] of 7 (5, 26) months, the median PFS for overall cohort was 17 (95%CI: 9.6-24.4) months. The median PFS for daratumumab plus IMiD group was 26 (95%CI: 6.0-46.0) months, which was significantly better than that in monotherapy or dexamethasone group [12 (95%CI: 3.5-20.5) months] (HR=0.231, 95%CI: 0.075-0.715, P=0.011). Higher diagnosis age was the risk factor of progression (HR=1.085, 95%CI: 1.016-1.158, P=0.014), while more cycles of daratumumab treatment was the protective factor of progression (HR=0.669, 95%CI: 0.495-0.904, P=0.009). There was no significant influence of daratumumab dosage on progression (high dosage vs low dosage, HR=1.016, 95%CI: 0.221-4.668, P=0.984). The median OS for overall cohort was 26 (95%CI: 13.1-38.9) months. Higher serum calcium was the independent risk factor of death (HR=12.190, 95%CI: 1.170-127.048, P=0.037). There was no significant influence of daratumumab dosage on death (high dosage vs low dosage, HR=0.818, 95%CI: 0.171-3.917, P=0.802). Adverse events included infections (43.2%, 16/37), infusion-associated reactions (29.7%, 11/37), and thrombocytopenia (27.0%, 10/37). Conclusions: Daratumumab is effective to treat RRMM. The dosage of daratumumab has no significant influence on prognosis when used in combined treatment. The incidence of adverse events is relatively low, with a favorable safety profile.

VP.29 Safety analysis of home-based enzyme replacement therapy with alglucosidase alfa in Pompe disease; a prospective study

Pompe disease is a progressive lysosomal storage disease treated with life-long weekly or biweekly enzyme replacement therapy (ERT). Home-based ERT diminishes the burden of treatment in Pompe patients and has been provided in the Netherlands since 2008. The COVID-19 pandemic has prompted the need for home-based ERT. We conducted a prospective survey to map infusion associated reactions (IARs) and validate safety of home-based ERT during one year. Patients with Pompe disease currently receiving alglucosidase alfa infusions at home were included. Prospective data on the occurrence, severity and management of IARs related to the home-infusion of alglucosidase alfa were collected by means of questionnaires. Patients received this questionnaire every three months during one year. Data on 120 patients were collected; 18 classic infantile, 18 childhood onset, and 84 adult onset Pompe patients. In total 116 of these patients filled in 423 questionnaires (overall response rate: 88%). Health problems during or within 48 hours from infusion were reported 27 times in 17 patients (5 classic infantile, 1 childhood onset, 11 adult onset). None of the infusion associated reactions that occurred warranted immediate care in hospital. Our data demonstrate that home-based ERT in Pompe disease is safe as few IARs occurred and those that occurred could be managed with no or minor interventions. Insights gained from this study can be used as a base for implementation of home-infusions in other countries and for further optimization of the protocol for home-based therapy with ERT in Pompe disease.

Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial

Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine. This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m2 intravenously on days 1 and 2, repeated after 28 days), followed by an induction and a maintenance with obinutuzumab (1000 mg intravenously on days 1-2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2-6 and every 12 weeks in the maintenance phase), acalabrutinib (100 mg orally twice daily continuously from induction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day). Eligible patients were aged 18 years or older with an ECOG performance score 0-2 and had relapsed or refractory chronic lymphocytic leukaemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria. The primary endpoint was uMRD (<10-4) in peripheral blood at the end of induction treatment assessed centrally at the final restaging, 12 weeks after the start of the last induction cycle. As per protocol, all patients with more than two induction cycles were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT03787264, and is ongoing. Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male, 21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity-race data was not collected. At data cutoff (Feb 25, 2021), all patients had completed the induction treatment. 34 patients (76%; 95% CI 61-87, p=0·26) had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff, 32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD. After a median observation time of 13·8 months (IQR 10·4-18·4), there were two (4%) Richter transformations, but no progressions and no deaths observed. The most common adverse events of grade 3 and 4 during the entire treatment were thrombocytopenia and neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections (five [11%] of 45 patients each, grade 3 adverse events only), infusion-associated reactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients). With 76% of patients achieving uMRD in peripheral blood, this trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs. Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended. Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie.