MDS-Related Anemia Is Associated with Impaired Quality of Life but Improvement Is Not Always Achieved by Increased Hemoglobin Level.

Quality of life is impaired in MDS, but the role of hemoglobin level is unclear. To study the Hb-QoL correlation at diagnosis and 1 year later, patients filled out the EQ-5D questionnaire, assessing their mobility, self care, daily activities, pain/discomfort, and anxiety/depression, using scores of 0 (normal), 1 (mild/moderate), or 2 (poor). They also evaluated their health using a visual analogue scale, scoring from 0 (poor) to 100 (excellent). The anemia subgroups were: none/normal (Hb ≥ 12.5 g/dL), mild (10 ≤ Hb < 12.5), moderate (9 ≤ Hb < 10), severe (8 ≤ Hb < 9), or very severe (Hb < 8). LR-MDS patients (n = 127) and inpatient controls (n = 141) participated. The anemic patients had a poor QoL and the MDS patients had a lower QoL with a lower Hb. The controls had no QoL difference among the various anemia subgroups. In addition, the MDS QoL sharply decreased with an Hb of < 9. The MDS patients showed a wide QoL variability, i.e., different QoL scores in the same Hb subgroup, suggesting that other factors affect QoL (e.g., age and comorbidities). After 1 year (n = 61), the QoL was still poor for most MDS patients (including 27 patients with an increased Hb). In summary: (1) a poor QoL in MDS-anemia is non-linear, suggesting other influencing factors on QoL. (2) The sharp QoL drop with Hb < 9 g/dL challenges the transfusion Hb threshold. (3) The QoL in anemic MDS patients might differ from that in non-MDS patients. (4) Raising Hb, while recommended, does not guarantee an improved QoL.

Real-World Experiences with Taliglucerase Alfa Home Infusions for Patients with Gaucher Disease: A Global Cohort Study.

Taliglucerase alfa is an enzyme replacement therapy approved for Gaucher disease. We assessed the duration/compliance/safety of such home infusions in commercial use in four countries where home infusion programs are available. The treatment duration/compliance study included 173 patients (Israel, 58; US, 61; Brazil, 48; Australia, 6) who received ≥1 taliglucerase alfa home infusion through 6/2021. The median age at home therapy initiation was 38 (range, 2-87) years; 58% were females. The median treatment duration (at home) was 2.7 (range, 0.04-9.0) years. The annual compliance rate was stable (≥95%) throughout the study period. A search of the Pfizer global safety database (through 6/2021), identified 19 adverse events (AEs) as related to "definite home use" and 14 to "possible home use" of taliglucerase alfa; 42.4% of these AEs were serious; none were fatal. Twelve serious AEs in five separate case reports were considered treatment related: one case of chest discomfort/pain and hypertension and one case of erythema associated with a toe blister, for which causality could not be excluded; pain in extremity; projectile vomiting and chills, alongside excessive eye blinking; and an infusion-related AE (pruritus). In conclusion, this real-life global study demonstrated that taliglucerase alfa home infusions are safe with high compliance rates.

Population-based cohort of 500 patients with Gaucher disease in Israel.

OBJECTIVE: To characterise a population-based cohort of patients with Gaucher disease (GD) in Israel relative to the general population and describe sociodemographic and clinical differences by disease severity (ie, enzyme replacement therapy [ERT] use). DESIGN: A cross-sectional study was conducted. SETTING: Data from the Clalit Health Services electronic health record (EHR) database were used. PARTICIPANTS: The study population included all patients in the Clalit EHR database identified as having GD as of 30 June 2014. RESULTS: A total of 500 patients with GD were identified and assessed. The majority were ≥18 years of age (90.6%), female (54.0%), Jewish (93.6%) and 34.8% had high socioeconomic status, compared with 19.0% in the general Clalit population. Over half of patients with GD with available data (51.0%) were overweight/obese and 63.5% had a Charlson Comorbidity Index ≥1, compared with 46.6% and 30.4%, respectively, in the general Clalit population. The majority of patients with GD had a history of anaemia (69.6%) or thrombocytopaenia (62.0%), 40.4% had a history of bone events and 22.2% had a history of cancer. Overall, 41.2% had received ERT. CONCLUSIONS: Establishing a population-based cohort of patients with GD is essential to understanding disease progression and management. In this study, we highlight the need for physicians to monitor patients with GD regardless of their ERT status.

Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate-to-severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Biomarker median percent changes from baseline were -91% for chitotriosidase, -87% for CCL18, -92% for glucosylsphingosine, and -80% for plasma glucosylceramide. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naïve patients with Gaucher disease.

Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, -0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm3). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187.

The role of high density lipoprotein in Type 1 Gaucher disease.

Type I Gaucher Disease (GD1) is known to be associated with hypocholesterolemia and reduced levels of low density lipoprotein (LDL) and high density lipoprotein (HDL). In this study we aimed to correlate disease severity with HDL levels and to evaluate the effect of enzyme replacement therapy (ERT) on HDL levels as well as estimating the frequency of cardiovascular events in GD. Two groups of GD1 patients were evaluated: 30 untreated and 36 patients on ERT. Disease severity, biomarkers of GD and lipid levels were evaluated in the two groups. The Zimran Severity Score Index (SSI) was used to estimate disease severity and the effect of ERT on HDL levels was evaluated, as well as the frequency of cardiovascular disease. GD1 patients with more severe disease (SSI median 11) had significantly lower levels of HDL (median 23mg/dL), compared to patients with milder (SSI median 4.5) disease (median 37mg/dL p=0.001). HDL levels increased after ERT. Despite lower HDL levels in patients with more severe disease, a low frequency of cardiovascular events was detected. HDL level should be used in GD as a biomarker for diagnosis, monitoring and estimation of ERT effect.

Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndromes (MDS)-ViLen-01 protocol.

Azacitidine treatment is effective in higher risk MDS (HR-MDS), with less than 50 % response, lasting 2 years. Aza and lenalidomide (Len) have a potential synergistic effect. ViLen-01 phase IIa trial includes 6-month induction (Aza 75 mg/m(2)/day, days 1-5, Len 10 mg/day, days 6-21, every 28 days), 6-month consolidation (Aza 75 mg/m(2)/day, days 1-5, every 28 days), and 12-month maintenance (Len 10 mg/day, days 1-21, every 28 days). Response was evaluated according to IWG criteria. Totally, 25 patients enrolled, with an average of 76.3 years old (60-87), and 88 % with major comorbidities. Thirteen patients completed induction, 7 proceeded for consolidation, and 2 for maintenance. The overall response rate (ORR) was 72 % (18/25), with 6 (24 %) for CR, 3 (12 %) for marrow CR, and 9 (36 %) for hematologic improvement (HI). The 7 non-responding patients were on the study 3 days to 4.1 months. At 6 months, 4 of 6 evaluable patients achieved complete cytogenetic response and 2 with del (5q) at diagnosis. Adverse events (AEs) were as expected in these patients: grades III-IV, mainly hematologic-thrombocytopenia (20 patients) and neutropenia (13 patients). The common non-hematologic AEs were infections (14 patients), nausea (7), vomiting (7), diarrhea (7), and skin reactions (5). The median progression-free survival (PFS) was 12 ± 1.36 months, with median overall survival (OS) of 12 ± 1.7 months. Quality of life (FACT questionnaire) data were available for 12 patients with a tendency towards improved QoL. This trial with elderly HR-MDS patients with an expected poor prognosis demonstrates a high (72 %) response rate and a reasonable expected safety profile but a relatively short PFS and OS.

Long-term efficacy and safety results of taliglucerase alfa up to 36 months in adult treatment-naïve patients with Gaucher disease.

Taliglucerase alfa is an intravenous enzyme replacement therapy approved for treatment of type 1 Gaucher disease (GD), and is the first available plant cell-expressed recombinant therapeutic protein. Herein, we report long-term safety and efficacy results of taliglucerase alfa in treatment-naïve adult patients with GD. Patients were randomized to receive taliglucerase alfa 30 or 60 U/kg every other week, and 23 patients completed 36 months of treatment. Taliglucerase alfa (30 U/kg; 60 U/kg, respectively) resulted in mean decreases in spleen volume (50.1%; 64.6%) and liver volume (25.6%; 24.4%) with mean increases in hemoglobin concentration (16.0%; 35.8%) and platelet count (45.7%; 114.0%), and mean decreases in chitotriosidase activity (71.5%; 82.2%). All treatment-related adverse events were mild to moderate in intensity and transient. The most common adverse events were nasopharyngitis, arthralgia, upper respiratory tract infection, headache, pain in extremity, and hypertension. These 36-month results of taliglucerase alfa in treatment-naïve adult patients with GD demonstrate continued improvement in disease parameters with no new safety concerns. These findings extend the taliglucerase alfa clinical safety and efficacy dataset. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:656-660, 2016. © 2016 Wiley Periodicals, Inc.

Enzyme replacement therapy with taliglucerase alfa: 36-month safety and efficacy results in adult patients with Gaucher disease previously treated with imiglucerase.

Taliglucerase alfa is the first available plant cell-expressed human recombinant therapeutic protein. It is indicated for treatment of patients with type 1 Gaucher disease (GD) in adult and pediatric patients in several countries. Study PB-06-002 examined the safety and efficacy of taliglucerase alfa for 9 months in patients who previously received imiglucerase. The results of adult patients from Study PB-06-002 who continued receiving taliglucerase alfa in extension Study PB-06-003 for up to 36 months are reported here. Eighteen patients received at least one dose of taliglucerase alfa in Study PB-06-003; 10 patients completed 36 total months of therapy, and four patients who transitioned to commercial drug completed 30-33 months of treatment. In patients who completed 36 total months of treatment, mean percent (±standard error) changes from baseline/time of switch to taliglucerase alfa to 36 months were as follows: hemoglobin concentration, -1.0% (±1.9%; n = 10); platelet count, +9.3% (±9.8%; n = 10); spleen volume measured in multiples of normal (MN), -19.8% (±9.9%; n = 7); liver volume measured in MN, +0.9% (±5.4%; n = 8); chitotriosidase activity, -51.5% (±8.1%; n = 10); and CCL18 concentration, -36.5 (±8.0%; n = 10). Four patients developed antidrug antibodies, including one with evidence of neutralizing activity in vitro. All treatment-related adverse events were mild or moderate and transient. The 36-month results of switching from imiglucerase to taliglucerase alfa treatment in adults with GD provide further data on the clinical safety and efficacy of taliglucerase alfa beyond the initial 9 months of the original study. www.clinicaltrials.gov identifier NCT00705939. Am. J. Hematol. 91:661-665, 2016. © 2016 Wiley Periodicals, Inc.

Management of women with Gaucher disease in the reproductive age.

Gaucher disease (GD) is a lysosomal disorder caused by inherited deficiency of glucocerebrosidase, resulting in the accumulation of glucocerebroside in macrophages, termed "Gaucher cells" (GCs), leading to multiorgan involvement, with hepatosplenomegaly, cytopenias, pulmonary hypertension and osseous complications. The characteristic feature of GD is the organ GCs infiltration compromising their function by inducing local inflammation, infarcts and fibrosis. Enzyme replacement therapy (ERT) available for over two decades improves hematological abnormalities, reverses the visceromegaly, ameliorates bone symptoms and prevents further skeletal complications. GD affects most female events during the reproductive age, particularly, fertility, pregnancy, delivery and puerperium. While pregnancy in GD may exacerbate disease manifestations, the disease may have deleterious effect on female reproductive health milestones. ERT has a beneficial effect on the pregnancy outcome in terms of the risk of spontaneous abortion and GD-related complications, particularly bleeding during delivery and postpartum. Treatment approaches and management aspects of reproductive age events are reviewed hereby, with a focus on the outcome improvement of pregnancies, deliveries and postpartum period in GD patients.

Impaired migration capacity in monocytes derived from patients with Gaucher disease.

Gaucher disease (GD) is characterized by glucocerebroside (GC) accumulation due to defective activity of the glucocerebrosidase (GlcCerase) enzyme. Monocytes and macrophages exhibit the highest GlcCerase activity and are most prominently affected by GC engorgement. As GD patients tend to exert various immune system-related changes, this study was designed to investigate potential effects of monocyte dysfunction on these alterations. Monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of untreated GD patients and healthy volunteers. Monocyte migration capacity towards SDF1α was assessed. The GD patients exhibited reduced numbers of monocytes and decreased capability of SDF1α-dependent monocyte migration. Evaluation of CXCR4, the SDF1α receptor, revealed reduced expression of surface CXCR4 on GD-derived monocytes, despite similar CXCR4 mRNA transcript levels in the monocytes of healthy volunteers and GD patients. Reduction of surface CXCR4 was accompanied by increased intracellular CXCR4 levels in patient monocytes. This elevated intracellular CXCR4 might reflect significantly increased SDF1α concentrations characterizing patients' serum and the lysosomal impairment of GD, resulting in decreased degradation of CXCR4. Different distributions of CXCR4 expression observed in the two groups explain impaired SDF1α-dependent monocyte migration. Reduced numbers and impaired migration capacity of GD-derived monocytes could contribute to abnormal inflammation and GD-associated immune alterations seen in these patients.

Hemorrhagic aspects of Gaucher disease.

Gaucher disease (GD) is an inherited lysosomal disorder, originating from deficient activity of the lysosomal enzyme glucocerebrosidase (GCase). Normally, GCase hydrolyzes glucocerebroside (GC) to glucose and ceramide; however, impaired activity of this enzyme leads to the accumulation of GC in macrophages, termed "Gaucher cells." Gaucher disease is associated with hepatosplenomegaly, cytopenias, skeletal complications and in some forms involves the central nervous system. Coagulation abnormalities are common among GD patients due to impaired production and chronic consumption of coagulation factors. Bleeding phenomena are variable (as are other symptoms of GD) and include mucosal and surgical hemorrhages. FOUR MAIN ETIOLOGICAL FACTORS ACCOUNT FOR THE HEMOSTATIC DEFECT IN GD: thrombocytopenia, abnormal platelet function, reduced production of coagulation factors, and activation of fibrinolysis. Thrombocytopenia relates not only to hypersplenism and decreased megakaryopoiesis by the infiltrated bone marrow but also to immune thrombocytopenia. Autoimmunity, especially the induction of platelet antibody production, might cause persistent thrombocytopenia. Enzyme replacement therapy reverses only part of the impaired coagulation system in Gaucher disease. Other therapeutic and supportive measures should be considered to prevent and/or treat bleeding in GD. Gaucher patients should be evaluated routinely for coagulation abnormalities especially prior to surgery and dental and obstetric procedures.

A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase.

Taliglucerase alfa is a ß-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9-60U/kg body weight) and regimen of administration (every 2weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.

Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat.

OBJECTIVE: Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). MATERIALS AND METHODS: Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18-55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. RESULTS: Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9% (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of -1.6 (1.1) to -0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56%) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42%) patients had focal bone lesions, which remained stable, and 7/19 (37%) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. CONCLUSIONS: Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1.

Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 years of treatment.

Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naïve patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of eliglustat reported at 1 and 2 years to 4 years.

Hypercoagulability, parkinsonism, and Gaucher disease.

Gaucher disease (GD) is a lysosomal disorder caused by inherited deficiency of glucocerebrosidase (GCase), resulting in the accumulation of glucocerebroside in macrophages, termed "Gaucher cells," leading to multiorgan involvement, with hepatosplenomegaly, cytopenias, pulmonary hypertension, and skeletal complications. Various mutations, encoding the GCase gene, cause acute or chronic neuronopathic forms of the disease. The hallmark of GD is the macrophages infiltrating organs, bone marrow, and nervous system compromising their function by inflammation, infarcts, fibrosis, and neuronal damage. Coagulation abnormalities are frequent among GD patients due to reduced production and chronic consumption of coagulation factors. Splenic and bone infarcts often occur in GD patients, but hypercoagulability is not frequent. Detection of thrombophilic risk factors in GD patients may predict a more severe course of the disease. Clinical and genetic studies revealed an association between reduced GCase activity in carriers of GD mutations and GD patients and occurrence of Parkinson disease (PD) and showed that GCase gene mutations are risk factors for PD development. The mechanisms underlying the association of PD and GD are not yet elucidated and should be further explored, particularly the potential involvement of inflammation and coagulation in the neurovascular unit.

Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease.

Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell-derived recombinant human ß-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: -31.9, -21.8) in the 30-unit dose group and 38.0% (95% CI: -43.4, -32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease.