
Gaucher disease (OMIM 606463) is an inherited metabolic disorder caused by deficiency of the lysosomal enzyme acid β-glucocerebrosidase with consequential accumulation of the substrate, glucosylceramide, and its unacylated derivative, glucosylsphingosine, in lysosomes of tissue macrophages [1,2]. Clinical presentations include hepatosplenomegaly, anemia, thrombocytopenia, and bone disease [1]. Enzyme replacement therapy (ERT) has been a standard therapy of Gaucher disease for 25 years. However, life-long alternate-week infusion of deficient enzyme limits patients’ quality of life. Eliglustat is an oral substrate reduction therapy (SRT) approved in the United States in 2014 and the European Union in 2015 for adults with Gaucher disease type I (GD1) who are extensive, intermediate, or poor
In Korea, eliglustat was approved since 2018. Here we report two-year experience of eliglustat therapy in three adult patients with GD1 who were stabilized on over 20-year long-term ERT.
Three adult Korean patients (one female and two males) from two families of GD1 were enrolled this study. Medical history, clinical and biochemical parameters of the patients were collected and evaluated by retrospective review of medical records at every 3, 6, or 12 month after switch to SRT from ERT. The clinical parameters included hemoglobin concentration, platelet count, and bone mineral density (BMD) measured by dual-energy x-ray absorptiometry. Serum angiotensin converting enzyme, serum total acid phosphatase, and glucosylsphingosine (lyso-gb1) concentration in dried blood spot were assessed as biomarker reflecting the activity of GD1. Adverse events were collected and assessed through regular follow-up in outpatient clinic every 1-2 months. The patients were educated for the drug interactions and avoidance of grapefruit during SRT. The drug adherence were monitored mainly by patients’ self-report supported by clinical and biochemical parameters. This study was approved by the Institutional Review Board of the Ajou University Hospital (AJIRB-MED-18-364).
The baseline clinical features are summarized in Table 1. Patient 1 and 2 were siblings diagnosed with GD1 carrying the compound heterozygous mutation of
Patient 2 was 41-year old male diagnosed GD1 at 18 years old by family screening. He had mild thrombocytopenia and splenomegaly at diagnosis. His genotype was same with patient 1. ERT with imiglucerase was started at 20 years of age and maintained his clinical and biochemical parameters stable for more than 20 years without any long-term complications of GD. He switched to eliglustat therapy at 40 years old after evaluation of eligibility (
Patient 3 was 31-year old male diagnosed Gaucher disease at 2 years old by severe anemia, thrombocytopenia and hepatosplenomegaly. He had compound heterozygous mutations in GBA (p.[Gly46Glu];[Leu444Pro]) and the β-glucocerebrosidase activity in leukocyte was 1.62 nmoL/hr/mg prot (reference ≥8.7). He had splenectomy when he was 3 years old. In 1998, ERT was started at 9 years of age and his clinical and biochemical parameters maintained stable for more than 20 years without any long-term complications of GD. After graduating the university, he got job and the ERT compliance was decreased to once a month due to the difficulties of absence. He switched to eliglustat therapy at 30 years old after evaluation of eligibility (
In 2017, Cox et al. [8] demonstrated that eliglustat was non-inferior to imiglucerase in maintaining the clinical parameters stable up to 4 years. Mean absolute values for hemoglobin concentration, platelet count, spleen volume, liver volume, and lumbar spine and femur Z scores remained stable over 4 years. Biomarkers for disease activity were also found to be stable over time. Quality-of-life measures showed that the quality of life that they had achieved after a mean of 10 years on enzyme therapy was maintained while they were taking eliglustat therapy in the long term [8]. And, recent pooled analysis of long-term adverse event profile from four completed trials of eliglustat reported that the majority of the most frequently reported treatment-related adverse events were mild or moderate, transient, and occurred only once per patient [9].
Although the follow-up period was relatively short (12 months), this study also demonstrated that the hematologic parameters remained stable by switching to SRT in all three patients with GD1 who were stabilized with long-term ERT. One of the limitation of this study is that the quality-of-life measurement, the important parameter of SRT effectiveness, did not assessed. Notably, the lumbar spinal BMD T scores showed further improvement after SRT in all three patients although the femur BMD T scores were maintained stable (Table 2). It is uncertain whether the improvement of lumbar spinal BMD was resulted from SRT or not, because the follow-up period was too short to draw a confirmative conclusion. Further long-term follow-up data is needed with careful monitoring of BMD.
The 8-year long-term response of biomarkers (chitotriosidase, CCL18, lyso-Gb1, and Gb1) to eliglustat was consistent with clinical parameters, which were highly elevated in baseline, were reduced by >85% [7]. Lyso-Gb1 is increasingly recognized as a highly specific and sensitive biomarker of GD with direct involvement in disease pathogenesis [10,11]. Despite the lyso-Gb1 level during ERT was unavailable in our patients, lyso-Gb1 remained stable during one-year of eliglustat therapy reflecting the stable disease activity. The significant reduction of lyso-Gb1 after initiation of ERT or SRT has been demonstrated, although the reduction becomes less robust over time after the maximal change rate [10-13]. Lyso-Gb1 was also useful for monitoring drug compliance during SRT. Recently, Hurvitz et al. [14] reported that lyso-Gb1 could reflect treatment response and detect treatment failures and compliance issues. In contrast to ERT, eliglustat is an oral drug and monitoring the drug compliance depends mainly on the patient’s statements. Measuring lyso-Gb1 and sharing the result with the patient (especially patient 2 in this study) was effective for educating and emphasizing the drug adherence.
Because eliglustat is one of the newly introduced drug, concerns about drug-drug or drug-food interactions were arose not only from the patients but also the physicians in real-world setting. The patient 1 decided to return to ERT because of uncertain concerns about possible drug interactions after suffering acute illness needs concurrent medication. As with many other oral drugs, eliglustat is metabolized primarily through the CYP2D6 pathway [15]. Dosing in the drug label is based on the
This study described the one-year experience of eliglustat therapy in three adult patients with GD1 who were clinically stabilized by over 20-year ERT. Although more long-term data is needed, eliglustat therapy was generally tolerated and the clinical parameters were remained stable. Considering the merits of oral drug, eliglustat could be one of the treatment option in eligible patients with GD1. Furthermore, education and caution for drug interaction and compliance is needed not only for patients but also physician for successful switching and achieving treatment goals.
The authors declare that they do not have any conflicts of interest.
Baseline clinical features of the patients
Patient 1 | Patient 2 | Patient 3 | |
---|---|---|---|
Sex/age (yr) | F/43 | M/41 | M/31 |
Age at diagnosis | 11 | 18 | 2 |
β-glucocerebrosidase activity in leukocyte (reference ≥8.7 nmoL/hr/mg prot) | 0.0 | 0.0 | 1.62 |
Genotype | p.[Gly46Glu];[Phe213Ile] | p.[Gly46Glu];[Phe213Ile] | p.[Gly46Glu];[Leu444Pro] |
History of surgery (age at surgery) | Splenectomy (16) | None | Splenectomy (3) |
Bilateral hip replacement (17) | |||
Cesarean section (39) | |||
Cholecystectomy (41) | |||
ERT duration before SRT (yr) | 22 | 21 | 22 |
Hematologic parameters | In normal range | In normal range | In normal range |
Skeletal involvement | AVN of femoral heads | Osteopenia | Osteopenia |
Osteopenia |
F, female; M, male; ERT, enzyme replacement therapy; SRT, substrate reduction therapy; AVN, avascular necrosis.
Changes of BMD T score during one-year eliglustat therapy
Patient 1 | Patient 2 | Patient 3 | ||||
---|---|---|---|---|---|---|
0 m | 12 m | 0 m | 12 m | 0 m | 12 m | |
Spine L1-L4 | –1.0 | 0.1 | –1.2 | –0.4 | –2.3 | –1.9 |
Femur neck | N/Aa | N/Aa | 0.5 | 0.3 | 0.3 | 0.5 |
Femur total | N/Aa | N/Aa | 0.9 | 0.9 | 0.8 | 1.2 |
BMD, bone mineral density; N/A, not available.
afemoral BMD T scores were not available due to total hip replacement surgery in patient 1.
![]() |
![]() |