Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of <0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (<0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of <0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

Download Full-text

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Blood ◽

10.1182/blood-2005-12-5072 ◽

2006 ◽

Vol 108 (3) ◽

pp. 830-835 ◽

Cited By ~ 102

Author(s):

Maaike de Fost ◽

Carla E. M. Hollak ◽

Johanna E. M. Groener ◽

Johannes M. F. G. Aerts ◽

Mario Maas ◽

...

Keyword(s):

Bone Marrow ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Bone Marrow Involvement ◽

Median Dose ◽

Long Term Outcome ◽

Enzyme Replacement ◽

Type 1 Gaucher Disease

AbstractDosing of enzyme replacement therapy (ERT) for Gaucher disease type 1 is still a subject of debate and varies from 15 to 130 U/kg/mo, making a huge economic difference of US $70 000 to US $380 000 (€55 000-300 000) per patient per year. To investigate whether this difference in dosing ultimately translates into a different response, we retrospectively compared long-term outcome of ERT at 2 large European treatment centers, Academic Medical Center, Amsterdam, The Netherlands (n = 49, median dose, 15-30 U/kg/4 wks) and Heinrich-Heine University, Duesseldorf, Germany (n = 57, median dose, 80 U/kg/4 wks). These adult cohorts had a similar genetic background. All follow-up parameters were matched separately at baseline, to avoid bias with respect to disease severity. Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between both cohorts, whereas plasma chitotriosidase and bone marrow involvement by magnetic resonance imaging improved more quickly and was more pronounced in the higher-dosed group. Major bone complications rarely occurred in both groups. In conclusion, different dosing regimens of ERT do not affect outcome of hematologic and visceral parameters, but higher dosing leads to accelerated decrease of chitotriosidase and better objective bone response in adult type 1 Gaucher disease.

Download Full-text

Correlation of Bone Marrow Response with Hematological, Biochemical, and Visceral Responses to Enzyme Replacement Therapy of Nonneuronopathic (Type 1) Gaucher Disease in 30 Adult Patients

Blood Cells Molecules and Diseases ◽

10.1006/bcmd.2002.0511 ◽

2002 ◽

Vol 28 (2) ◽

pp. 209-220 ◽

Cited By ~ 41

Author(s):

Ludger Wilhelm Poll ◽

Jens-Albrecht Koch ◽

Reinhart Willers ◽

Hans Aerts ◽

Axel Scherer ◽

...

Keyword(s):

Bone Marrow ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Adult Patients ◽

Enzyme Replacement ◽

Type 1 Gaucher Disease

Download Full-text

Report on the Safety of Velaglucerase Alfa Enzyme Replacement Therapy in Patients with Type 1 Gaucher Disease and the Transition From Clinic to Home Infusions During Treatment Protocol HGT-GCB-058

Blood ◽

10.1182/blood.v118.21.1101.1101 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1101-1101

Author(s):

Gregory M Pastores ◽

Barry E Rosenbloom ◽

Neal J Weinreb ◽

Ozlem Goker-Alpan ◽

Rebecca Mardach ◽

...

Keyword(s):

Board Of Directors ◽

Gaucher Disease ◽

Research Funding ◽

Treatment Protocol ◽

Home Therapy ◽

Advisory Committees ◽

Enzyme Replacement ◽

Home Infusion ◽

Type 1 Gaucher Disease

Abstract Abstract 1101 BACKGROUND: Type 1 Gaucher disease (GD) is an inherited storage disease characterized by acid-β-glucosidase deficiency and the accumulation of glucosylceramide in the mononuclear phagocyte system. Hematologists are commonly the specialists to whom affected individuals present; findings may include anemia, thrombocytopenia, splenomegaly, hepatomegaly, and skeletal and bone marrow pathology. HGT-GCB-058 was a multicenter treatment protocol initiated at the request of the US Food and Drug Administration (FDA) in 2009 (ClinicalTrials.gov identifier NCT00954460). It provided velaglucerase alfa, then an investigational drug, to patients with type 1 GD who would otherwise have experienced a disruption or delay in receiving enzyme replacement therapy (ERT) due to a global supply shortage of imiglucerase at that time. OBJECTIVE: We report safety results in patients who received up to 12 months of velaglucerase alfa in protocol HGT-GCB-058, and the transition from administration at the clinical site to home infusions. METHODS: To enroll, patients had to be aged >2 years, with a documented diagnosis of type 1 GD and no history of an anaphylactic or anaphylactoid reaction to ERT. Patients who were treatment-naïve received 60 U/kg (body weight) of velaglucerase alfa as an intravenous infusion every other week (EOW). Patients who were previously treated with imiglucerase (switch patients) received the same EOW dose of velaglucerase alfa as their prior imiglucerase treatment. Each patient could continue in the protocol until commercial therapy was available to him or her. Adverse events (AEs) were monitored throughout the patient's participation in the protocol. Switch patients were eligible for home therapy if they received their first 3 infusions, at the clinical site, in the absence of an infusion-related AE or treatment-related, serious AE (SAE). RESULTS: Across 23 centers, 211 patients were enrolled. The median age was 54 years (range 6–89 years); 8 patients were aged <18 years; 48% were male; 34% were splenectomized. There were 205 switch patients (the median prior imiglucerase exposure was 145 months [range 1–231 months]) and 6 treatment-naïve patients. All 211 patients received ≥1 infusion of velaglucerase alfa. By the end of 12 months, 203 patients had left the protocol; most patients transitioned to commercial velaglucerase alfa, which was approved by the FDA in 2010. The median duration of velaglucerase alfa treatment in the protocol was 182 days (range 1–365 days) for switch patients and 106 days (range 27–232 days) for treatment-naïve patients. Over 12 months, most AEs were mild or moderate in severity. Twenty severe AEs were reported in 11 patients, of which 5 – pain in extremity and fatigue in 1 patient, fatigue in 1 patient, and 2 instances of generalized pain in 1 patient – were considered treatment-related Table). Ten SAEs were reported in 7 patients, of which 1 (migraine) was considered treatment-related. The AEs leading to protocol discontinuation were: nausea, increased blood pressure (both treatment-related), and hip fracture (not treatment-related). The most common AEs were nasopharyngitis (n=15), headache (n=15), and nausea (n=12). After the first 3 infusions, 187 of the 205 switch patients were eligible for home therapy based on safety criteria. During the protocol, 54 patients received ≥1 home infusion. Home infusions were administered by qualified and trained medical personnel under the direction of the investigator. Patients' and investigators' preferences for home therapy were not captured in the protocol. CONCLUSIONS: Velaglucerase alfa was generally well-tolerated in a large, clinically heterogeneous group of patients with type 1 GD. Of 205 patients in treatment protocol HGT-GCB-058 who switched from imiglucerase, 91% met the safety criteria for early transition to home infusions and 26% received ≥1 home infusion, which supports home therapy as a treatment option depending on the patient's response and the recommendation of the treating physician. Disclosures: Pastores: Actelion: Research Funding; Amicus: Research Funding; Biomarin: Research Funding; Genzyme Corp: Research Funding; Protalix: Research Funding; Shire HGT: Research Funding. Rosenbloom:Genzyme Corporation: Educational Grant; Shire Pharmaceuticals: Research Funding, Speakers Bureau; Genzyme Corp: Research Funding, Speakers Bureau. Weinreb:Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amicus: Research Funding; Actelion: Speakers Bureau. Goker-Alpan:Shire HGT: Consultancy, Research Funding; Genzyme Corp: Research Funding, Speakers Bureau; Amicus: Research Funding; Pfizer-Protalix Biotherapeutics: Consultancy, Research Funding. Lipson:Kaiser-Permanente: Employment. Ibrahim:Shire HGT: Research Funding. Cohn:Shire HGT: Employment. Zahrieh:Shire HGT: Employment. Mistry:Shire: Research Funding.

Download Full-text