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 15.0 months [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.

Lessard LER ，Tard C ，Salort-Campana E ，Sacconi S ，Béhin A ，Bassez G ，Orlikowski D ，Merle P ，Nollet S ，Gallay L ，Bérard F ，Robinson P ，Bouhour F ，Laforêt P ... -  《-》

White matter lesions in treated late onset Pompe disease are not different to matched controls.

Genetic deficiency of α-1,4-glucosidase leads to multi-systemic glycogen storage and causes muscular disorder known as classic infantile Pompe disease (CIOPD) and late onset Pompe disease (LOPD). Treatment with recombinant human alglucosidase alfa is available as enzyme replacement therapy (ERT). Recently progressive white matter lesions (WML) have been observed as a new phenotype in CIOPD patients on treatment with ERT. To investigate the impact of disease and ERT for the development of WML in LOPD. WML were analysed in 19 treated LOPD patients and compared with findings of 38 matched controls. Patients median age was 54.4 years (range 19 to 82 years) with median disease duration of 7 years (range 2 to 40 years). Median ERT duration was 63 months (range 9 to 135 months). Grading of WML by Fazekas Score was not different in LOPD patients and controls: Mean of total Fazekas score in LOPD was 2.42 ± 2.40 and in controls 1.60 ± 2.64; p = 0.68. Also volume of WML was similar in patients and controls (mean 5.27 ml ± 5.88 and 7.89 ml ± 11.40 respectively, p = 0.35). Total Fazekas grade correlated directly with the age in LOPD patients (r = 0.60; p = 0.007) and in controls (r = 0.32; p = 0.04). There was a negative correlation of ERT duration and total Fazekas grade (r = -0.41; p = 0.04). The study suggests that WML in LOPD mainly result from concomitant cerebrovascular risk factors rather than from the Pompe disease itself.

Schneider I ，Hensel O ，Zierz S 《-》

Assessing the Role of Anti rh-GAA in Modulating Response to ERT in a Late-Onset Pompe Disease Cohort from the Italian GSDII Study Group.

Filosto M ，Cotti Piccinelli S ，Ravaglia S ，Servidei S ，Moggio M ，Musumeci O ，Donati MA ，Pegoraro E ，Di Muzio A ，Maggi L ，Tonin P ，Marrosu G ，Sancricca C ，Lerario A ，Sacchini M ，Semplicini C ，Bozzoni V ，Telese R ，Bonanno S ，Piras R ，Maioli MA ，Ricci G ，Vercelli L ，Galvagni A ，Gallo Cassarino S ，Caria F ，Mongini T ，Siciliano G ，Padovani A ，Toscano A ... -  《-》

Effects of short-to-long term enzyme replacement therapy (ERT) on skeletal muscle tissue in late onset Pompe disease (LOPD).

Pompe disease is an autosomal recessive lysosomal storage disorder resulting from deficiency of acid α-glucosidase (GAA) enzyme. Histopathological hallmarks in skeletal muscle tissue are fibre vacuolization and autophagy. Since 2006, enzyme replacement therapy (ERT) is the only approved treatment with human recombinant GAA alglucosidase alfa. We designed a study to examine ERT-related skeletal muscle changes in 18 modestly to moderately affected late onset Pompe disease (LOPD) patients along with the relationship between morphological/biochemical changes and clinical outcomes. Treatment duration was short-to-long term. We examined muscle biopsies from 18 LOPD patients at both histopathological and biochemical level. All patients underwent two muscle biopsies, before and after ERT administration respectively. The study is partially retrospective because the first biopsies were taken before the study was designed, whereas the second biopsy was always performed after at least 6 months of ERT administration. After ERT, 15 out of 18 patients showed improved 6-min walking test (6MWT; P = 0.0007) and most of them achieved respiratory stabilization. Pretreatment muscle biopsies disclosed marked histopathological variability, ranging from an almost normal pattern to a severe vacuolar myopathy. After treatment, we detected morphological improvement in 15 patients and worsening in three patients. Post-ERT GAA enzymatic activity was mildly increased compared with pretreatment levels in all patients. Protein levels of the mature enzyme increased in 14 of the 18 patients (mean increase = +35%; P < 0.05). Additional studies demonstrated an improved autophagic flux after ERT in some patients. ERT positively modified skeletal muscle pathology as well as motor and respiratory outcomes in the majority of LOPD patients.

Ripolone M ，Violano R ，Ronchi D ，Mondello S ，Nascimbeni A ，Colombo I ，Fagiolari G ，Bordoni A ，Fortunato F ，Lucchini V ，Saredi S ，Filosto M ，Musumeci O ，Tonin P ，Mongini T ，Previtali S ，Morandi L ，Angelini C ，Mora M ，Sandri M ，Sciacco M ，Toscano A ，Comi GP ，Moggio M ... -  《-》

First successful concomitant therapy of immune tolerance induction therapy and desensitization in a CRIM-negative infantile Pompe patient.

Enzyme replacement therapy (ERT) with alglucosidase alfa (rhGAA) has changed the fatal course of infantile Pompe disease, however, development of anti rhGAA antibodies and infusion-associated reactions (IAR) restrict the tolerability and effectiveness of the treatment. We describe a successful concomitant immune tolerance induction (ITI) and desensitization protocols in a cross-reactive immunologic material (CRIM) negative 7-month-old male patient. At the age of 5 months and eighth dose of the ERT, the patient developed IAR and his rhGAA specific IgE was negative however, his rhGAA specific IgG titer was as high as 12,800. ITI therapy to suppress antibody formation and a desensitization protocol was devised to be given concomitantly. At the end of 5-week therapy, his fatigue and weakness improved profoundly and a control antidrug antibody level decreased at 800. At the time of the patient's follow up, he was still on ERT with desensitization at the age of 15 months without any reactions. This is the first report in the literature applying concomitant ITI and desensitization protocols in a CRIM negative infantile-onset Pompe disease patient successfully, hence the importance of the case.

Emecen Sanli M ，Ertoy Karagol HI ，Kilic A ，Aktasoglu E ，Inci A ，Okur I ，Ezgu F ，Tumer L ... -  《-》