Long Term Outcomes of ERT in Children with Gaucher Disease. Spanish Experience

Background. Enzymatic replacement therapy (ERT) had modified the natural history of Gaucher disease (GD). Historically the GD patients had growth retardation; frequently spleen removal, and multiple bone complications. It is known that more than 70% of GD patients diagnosed in adulthood have bone complications. Nowadays we have learnt through clinical trials that patients treated regularly with ERT during childhood achieve a normal percentile of growing and avoid complications. In this report we are summarizing the Spanish experience in the last two decades treating children with GD in every day clinical practice.

Patients & Methods: From 376 patients included in the Spanish Registry of Gaucher Disease working since 1993, a total of 79 patients were diagnosed under18 years old, 26 of them were classified as GD type 2; 13 developed a GD3 during follow-up and 40 were classified as GD1. For the analysis we have only included GD1 and GD3 patients, 53 patients. Statistical analysis: Descriptive and frequency analysis were performed in a SSPS data base.

Results: Baseline characteristics: Gender: 18 females and 35 males. Mean age at diagnosis 5.8 y.o. (range 0.5-17), 78.4% (62) of cases were the initial case for familiar studies, mean age at start ERT 8.5 years (0.5-18), Mutational analysis: L444P/L444P was the most frequent genotype in GD3 and N370S heterozygosis in GD1, there was only one case with N370S homozygosis, Three patients were splenectomised before diagnosis and 60% underwent a bone marrow aspiration or biopsy and 3 liver biopsy during the initial workout. The paediatric Gaucher Score Index (PGSI) (Kallish S, Kaplan P 2012) shows: mild-disease: 62.5%, moderate: 31.25% and severe: 6.25%, missing data 5 patients. Mean chitotriosidase: 12,535 nmol.ml/h (871-49,031), hemoglobine: 11.4g/dL (6.9-17), 43% of patients presented anemia at diagnosis. Mean platelet count: 121 x10⁹ (12,363), 53% of patients presents with < 100 x10⁹ platelets. Bone assessment: 49% (26) of patients shows bone manifestations: Erlenmeyer flask deformity, 24.5%; Bone crisis, 13.2%; avascular necrosis, 5.6%; bone infiltration, 7.5%, Bone infarction: 3.7%; isolated bone pain, 13.2%. The mean follow-up was 13 y (2-21), 45 received ERT following diagnosis, mean years on therapy 13.2 (2-21). In first line: Alglucerase, 8.9% (4); Imiglucerase, 75.5% (34); Velaglucerase, 6.7% (3) and Taliglucerase 8.9% (4). Actual therapies: Imiglucerase: 47.1% (25); Velaglucerase: 17% (9); Taliglucerase: 3.7% (2); Miglustat: 7.5% (4), Eliglustat: 1.8% (1), no ERT/ loss of contact: 7.5%. Mean time on ERT: 13,2 years, twenty-one patients had received ERT during 15 or more years (15-21); 12 for > 10 years (12-14) and 11< 10 years (2-9). Actual status: mean haemoglobin levels: 13, 3g/dL, mean platelets count: 162 x10⁹, Chitotriosidase: 497 mg.prot.h, there are no patients with hepatomegaly and only 3 patients have splenomegaly. Events related to therapy: infusion reactions G3/4: 4, all patients had IgG specific antibodies, and all reactions occurs between 1 and 7 months after start therapy; abandonment 2; changes of ERT, 7 (excluding alglucerase to imiglucerase); related to disease: growth retardation 9 (bellow 25 percentile for age/high); bone crisis 3; joint replacement 1, osteopenia 2 cases (after 2 years on ERT), normalization of coagulation factors (VW,FV,FIX,FXI), others: early diabetes 1, early menarche 1, thyroiditis 1, sacroileitis 1, pregnancies 3, lost follow-up 4.

Conclusions: The incidence of GD related complications, especially bone complications, in paediatric patients on ERT is lower than in adults, probably related to early ERT onset. Endocrine complications are rare, difficult to correlate to ERT. Growth retardation was resolved with ERT in the majority of cases. The early onset of therapy in symptomatic child is highly recommended.