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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.

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.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when >= 75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

ObjectiveTo 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).DesignA cross-sectional study was conducted.SettingData from the Clalit Health Services electronic health record (EHR) database were used.ParticipantsThe study population included all patients in the Clalit EHR database identified as having GD as of 30 June 2014.ResultsA 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.ConclusionsEstablishing 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.

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.

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.

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.

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/mm3), 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 2years to 4years.

Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (

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.

Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg BID for one year during an open-label Phase 2 study [Blood 116(6):893-899, 2010]. We report further improvements after two years of treatment in 20 patients (11F/9M; mean age=33) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (p

Type 1 (non-neuronopathic) Gaucher disease was the first lysosomal storage disorder for which an effective enzyme replacement therapy was developed and it has become a prototype for treatments for related orphan diseases. There are currently four treatment options available to patients with Gaucher disease, nevertheless, almost 25% of Type 1 Gaucher patients do not gain timely access to therapy because of delays in diagnosis after the onset of symptoms. Diagnosis of Gaucher disease by enzyme testing is unequivocal, but the rarity of the disease and nonspecific and heterogeneous nature of Gaucher disease symptoms may impede consideration of this disease in the differential diagnosis. To help promote timely diagnosis and optimal management of the protean presentations of Gaucher disease, a consensus meeting was convened to develop algorithms for diagnosis and disease management for Gaucher disease.

Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease.Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers.All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations.Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

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.

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.

Type 1 Gaucher disease is considered the non-neuronopathic form of this autosomal recessively inherited lysosomal storage disease. We report the simultaneous occurrence of Gaucher disease with parkinsonian in four adult patients. The patients had a relatively early onset of parkinsonian manifestations, and their disease was rapidly progressive and refractory to therapy. Each had a different Gaucher genotype, although four alleles carried the common N370S mutation. No mutations were identified in the genes for parkin or alpha-synuclein. The concurrence of these two phenotypes, both in this series of patients and in others in the literature, suggests a shared pathway, modifier, or other genetic etiology.

Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, manifests with a continually expanding range of clinical features. Noting that a number of adult patients with type 1 Gaucher disease also had gallstones, we reviewed the clinical records of 66 adult patients evaluated at the National Institutes of Health with type 1 Gaucher disease. Twenty-one patients were identified who had either gallstones or a history of cholecystectomy. Of the 21 patients, 6 were male. The age at which stones were noted ranged from 19 to 70 years (mean 39 years). Thirteen of the patients had a cholecystectomy performed. Several different factors may contribute to the development of gallstones in these patients, including anemia, prior splenectomy, and hepatic involvement. Eleven of the patients were found to have chronic anemia. Fifteen of the patients underwent splenectomy. An increased biliary excretion of glucosylceramide could also contribute to cholelithiasis. To determine whether our findings were specific to our referral population, the medical records of a second series of 80 adult patients of Ashkenazi Jewish ancestry with type 1 Gaucher disease followed in Northern Israel were reviewed. Sixteen of these patients (5 male, 11 female) were also noted to have gallstones. Thus, the frequency of gallbladder involvement in patients with Gaucher disease appears to be greater than previously appreciated.

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.

Taliglucerase alfa is a β-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.

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.

The skin involvement of the myelodysplastic syndrome (MDS) can take the form of either a neoplastic infiltration or various non specific lesions. The occurrence of these lesions may be the presenting feature of the disease (MDS) or may herald its progression to acute leukemia. Recognition and early diagnosis have therapeutic and prognostic significance.

S88 Volume 29 Supplement C Hematologic and Hemato-Oncologic Aspects of Gaucher Disease Derralynn Hughes, MA, DPhil, MRCP, MRCPath1; Maria Domenica Cappellini, MD2; Marc Gabriel Berger, MD, PhD3; Jan Van Droogenbroeck, MD4; Maaike de Fost, MD5; Dragana Janic, MD, PhD6; Theodore Marinakis, MD, PhD7; Hanna Rosenbaum, MD8; Jesus Villarubia, MD, PhD9; Elena Zhukovskaya, MD10; and Carla Hollak, MD5 1Lysosomal Storage Diseases Unit, Department of Academic Haematology, Royal Free Hospital and University College Medical School, London, United Kingdom; 2Department of Internal Medicine, Policlinico Foundation IRCCS, University of Milan, Milan, Italy; 3Department of Hematology, CHU Hotel-Dieu, Clermont-Ferrand, France; 4Department of Hematology, AZ St. Jan AV, Brugge, Belgium; 5Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 6University Children’s Hospital, University of Belgrade, Belgrade, Serbia; 7The Hellenic Collaborative Working Group of Hematologists on Gaucher Disease, Athens, Greece; 8Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center and Bruce Rappaport Faculty of Medicine, Haifa, Israel; 9Ramon and Cajal Hospital, Servicio de Hematologia, Madrid, Spain; and 10State Medical Academy, Chelyabinsk, Russia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon α (IFNα) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNα-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNα therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNα therapy far better than the cytogenetic response.

On page 5767 in the 24 November 2011 issue, there are errors in the affiliations. The affiliation of the eleventh author (Heitner) is misspelled. The correct affiliation is University of Witwatersrand. The affiliation of the last author (Aviezer) is incomplete. His academic affiliation, Faculty of

Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell–derived recombinant human β-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. This study was registered at www.clinicaltrials.gov as NCT00376168.

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (−38.5%; 95% CI = −43.5%-−33.5%), liver volume (−17.0%; 95% CI = −21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1. This study is registered at www.clinicaltrials.gov as #NCT00358150.

Current knowledge of the haematological and onco-haematological complications of type 1 Gaucher disease has been reviewed with the aim of identifying best clinical practice for treatment and disease management. It was concluded that: (i) Awareness of typical patterns of cytopenia can help clinicians distinguish haematological co-morbidities. (ii) Red blood cell studies and complete iron metabolism evaluation at baseline are recommended. (iii) Haemoglobin levels defining anaemia should be raised and used in Gaucher disease treatment and monitoring. (iv) Surgeons should be aware of potential bleeding complications during surgery in Gaucher patients. The higher incidence of multiple myeloma in Gaucher disease suggests that Gaucher patients should have their immunoglobulin profile determined at diagnosis and monitored every 2 years (patients 50 years). If monoclonal gammopathy of undetermined significance (MGUS) is found, general MGUS guidelines should be followed. Future studies should focus on the utility of early treatment to prevent immunoglobulin abnormalities and multiple myeloma

BACKGROUND: Amiodarone hydrochloride is classified as a Vaughan Williams class III antiarrhythmic agent, although class I, II, and IV effects may contribute to its favorable antiarrhythmic profile. It is associated with a wide variety of adverse effects, such as hypothyroidism, hyperthyroidism, interstitial pulmonary disease, hepatitis, coagulation disorders, skin photosensitivity, corneal microdeposits, alopecia, peripheral neuropathy, and cardiovascular arrhythmias. SUBJECTS: Bone marrow aspirations and biopsies were performed on two patients treated with amiodarone, on the first during a follow-up for myelofibrosis and on the second for a suspected lymphoproliferative disorder. Several bone marrow granulomas were found in both patients. The bone marrow specimens for tuberculosis and fungal stains were negative. CONCLUSIONS The temporal relationship between the amiodarone therapy and the development of two cases of asymptomatic bone marrow granuloma suggest the possibility that this antiarrhythmic agent is involved in the etiology of these granulomas. TRASFONDO Hidrocloruro de amiodarone es un agente antiarrítmico clase III en la clasificación Vaughan Williams, aunque posee también propiedades de las clases I, II, y IV. Este medicamento se ha relacionado con una gran variedad de efectos secundarios. Entre estos se encuentran hipotiroidismo, hipertiroidismo, enfermedad intersticial pulmonar, hepatitis, desórdenes de coagulación, fotosensitividad en la piel, microdepósitos en la córnea, alopecia, neuropatía periférica, y arritmias. En este artículo se informan dos casos asintomáticos de granulomas, en la médula ósea asociados al uso de amiodarone. SUJETOS Dos pacientes en tratamiento con amiodarone se sometieron a aspiración de la médula osea y biopsia. En ambos se encontró varios granulomas en la médula. Las muestras de médula ósea fueron negativas para tuberculosis y hongos. El primer caso fue una mujer que había sido diagnosticada en 1979 con un desorden mieloproliferativo pero que había estado asintomática por 10 años. En 1987 comenzó a recibir amiodarone y 18 meses después, en una biopsia de seguimiento, presentó granulomas de tipo epiteloide con necrosis nocaseosa. La paciente sólo utilizaba amiodarone y aspirina en ese momento. El segundo paciente fue otra mujer que comenzó a utilizar amiodarone 18 meses antes de ser sometida a una biopsia de la médula ósea para evaluar la posibilidad de un desorden inmunoproliferativo o linfoproliferativo. La biopsia demostró una médula hipercelular con megacariocitos atípicos y varios granulomas con células epiletoides pero sin necrosis, células gigantes ni fibrosis. CONCLUSIONES La relación temporal entre el inicio del tratamiento con amiodarone y el desarrollo de los granulomas sugiere la posibilidad de que este medicamento contribuya en la etiología de éstos. Se asume que el uso de este fármaco promueve la acumulación de fosfolípidos en los linfoblastos de la médula ósea lo cual resulta en el desarrollo de granulomas. Sin embargo, los mecanismos etiológicos por los cuales ocurre ésto no se conocen con exactitud. Aunque los granulomas aparentan estar asociados a amiodarone, no se puede concluir esto en forma definitiva ya que en el primer caso se continuó con el uso del medicamento y en el segundo caso no se repitió la biopsia al descontinuar el fármaco. El significado clínico, la prognosis y consecuencias de granulomas asintomáticas en la médula ósea en personas sin enfermedad subayacente no se conoce. La presencia de granulomas en la médula ósea es un hallazgo poco frecuente, por lo cual cuando ocurre se debe identificar la causa. OBJECTIF Rapporter deux cas de granulomes asymptomatiques de la moelle osseuse associés à l'utilisation de l'amiodarone. RÉSUMÉ DU CAS Deux patients traités avec de l'amiodarone 200 mg/jour pour 18 mois ont eu une aspiration de la moelle osseuse et une biopsie. Des granulomes de la moelle osseuse ont été identifiés chez ces deux patients. Les échantillons de la moelle osseuse étaient négatifs pour une tuberculose et des infections fongiques. CONCLUSIONS L'amiodarone est un agent antiarythmique de la classe III qui est associee à de nombreux effets indésirables. Les auteurs ont décrit la présence de granulomes asymptomatiques de la moelle osseuse chez deux patients sous traitement avec amiodarone. La relation temporale entre l'apparition des granulomes et la prise d'amiodarone suggère que ce médicament serait impliqué dans l'étiologie de ces granulomes.

Traumatic ulcerative granuloma with stromal eosinophilia (TUGSE) is a benign lesion of the oral mucosa of an unclear pathogenesis. We analyzed the profile of the inflammatory infiltrate in 12 cases of TUGSE by using immunohistochemical analysis and polymerase chain reaction-based repertoire analysis to detect T- and B-cell receptor gene rearrangements. The inflammatory infiltrate consisted in most cases of B and T lymphocytes, macrophages, abundant eosinophils, and large atypical cells. In 5 cases, CD30+ cells were found. Spectratyping analysis displayed a polyclonal rearrangement of the T-cell receptor g gene in 6 cases and oligoclonality in 5 cases. Monoclonality was observed in 1 case that also fulfilled histologic criteria for lymphoma. Healing was uneventful in all cases, including the one suspected of being lymphoma, with no recurrences in more than 2 years'follow-up. TUGSE can be regarded reactive. Some cases, however, may harbor a dominant clonal T-cell population; in these cases, long-term follow-up is mandatory.

Type I Gaucher disease (GD) the is characterized by hepatosplenomegaly, pancytopenia and skeletal complications due to the accumulation of glucocerebroside in macrophages. Thrombocytopenia is usually related to hypersplenism and infiltration of bone marrow by lipid-laden macrophages namely Gaucher cells. Enzyme replacement therapy (ERT) restores the hemoglobin and platelet count in GD patients. In GD ERT treated patients, manifesting persistent low platelet counts, immune thrombocytopenia (ITP) should be considered.Treatment of GD with concomitant ITP is a challenge. Splenectomy may worsen bone manifestations in GD patients and is controversial. Steroids should be used with caution because of possible induction of osteopenia and joints avascular necrosis. Thrombopoietin receptor analogues (TPO-RA) are therapeutic option in GD patients with ITP. Beneficial use of TPO-RA is reported in 2 cases. Patient 1: 39 YO male with new onset of purpura and low platelet count failed treatment with 1 mg/kg of Prednisone. Bone marrow biopsy (BM) showed Gaucher cells infiltration, numerous atypical megakaryocytes, normal erythropoiesis and myelopoiesis with no fibrosis. Low level of ß-glucocerebrosidase activity with compound heterozygosity for 84GG /R495H mutations, established the diagnosis of Type I GD. Low C4 and detection of IgG platelet antibodies added to the diagnosis of concomitant immune thrombocytopenia. ERT with taliglucerase alfa (ElelysoTM) 60 Units/kg/month was given with Prednisone for six weeks. Occurrence of retinal bleeding and purpura, with decrease of platelet count necessitated addition of high-dose IVIG with no response regarding platelet counts. Splenectomy was not considered due to known bony complication risk in splenectomised GD patients. Rituximab was given to prevent wet purpura recurrence with short response regarding platelet count. Romiplostim was initiated raising platelet count from 29,000/µL to 60,000/µL after 3 wks. and to 90,000/µL after 8 wks. enabling corticosteroids withdrawal. Same dose Romiplostim is maintained for the last 30 months with platelet counts of 90,000 - 110,000/µL with no bleeding events. Repeated BMB showed no increase in collagen fibrosis. Patient 2: 63 YO female patient diagnosed with Gaucher at age 33 with a history of purpura, ecchymosis, and occasional vaginal bleeding episodes. At age 53 the platelet count dropped to < 20,000/µL with presence of Anti Platelets Ab (IgG). BMB revealed megakaryocytic hyperplasia with atypical forms, focal infiltration by Gaucher cells and no fibrosis. Combined therapy by ERT (Imiglucerase® followed by Velaglucerase Alfa®), Prednisone (1mg/kg/d for 2 months) and one course of IVIG yielded no increase in platelet count. The patient refused Rituximab®. Romiplostim was initiated increasing platelet count to100,000/µL maintained throughout a year of follow up. Repeated BMB showed slight increase of fibrosis and marked hyperplasia of atypical megakaryocytes. Discussion: Thrombocytopenia is often present in GD and may be severe in approximately 15% of the patients. Persistent cytopenias may be caused by other underlying pathologies such as autoimmune disorders and are important to be recognized and addressed. Before ERT era GD patients with hypersplenism and severe cytopenia were splenectomised. Risks of splenectomy include serious bacterial infection and vascular complications limiting its use in chronic refractory ITP. Splenectomy is avoided in Gaucher patients, due to risk of exacerbating skeletal complications (bone infarcts, avascular necrosis). Stable bone marrow results regarding fibrosis in our patients are consistent with data from a recent 2-year follow-up of 100 ITP patients receiving Romiplostim treatment with no evidence of BM fibrosis. Conclusion: In patients with type I Gaucher disease and concomitant ITP, adjunctive treatment with Romiplostim was successful in maintaining haemostatic platelet counts with no adverse effects. Traditional treatment regimens of corticosteroids and splenectomy should be used with caution or avoided in GD patients due to possible aggravation of Gaucher skeletal disease and the risk of osteopenia and avascular necrosis resulting in increased morbidity in this cohort of patients. Use of TPO-RA should be considered in GD patients with ITP. Disclosures Off Label Use: Romiplostim in gaucher patients.

Mutations in the glucocerebrosidase (GBA) gene have been recently identified as contributory to Parkinson disease (PD) in Ashkenazi Jews. In the present study, the clinical characteristics of Ashkenazi patients with PD with GBA mutations (n = 40) were compared to those of Ashkenazi patients with PD without any known GBA mutation (n = 108). The overall clinical manifestations and age at disease onset did not differ in patients with GBA mutations compared to patients without mutations.

Taliglucerase alfa is an enzyme replacement therapy (ERT) approved in the USA, Israel, and Uruguay for adult patients with type 1 Gaucher disease (GD). Study PB-06-002 was a 9-month, phase 3, multicenter, open-label, switchover trial that evaluated safety and efficacy of taliglucerase alfa in patients with GD previously treated with imiglucerase for at least 2 years. Eligible patients entered a 12-week evaluation period to establish the stability of their disease based on hematologic parameters. For patients whose imiglucerase regimen was changed due to drug shortage, eligibility was based on historical data of disease stability. Patients with stable disease were then switched from imiglucerase to the same dose of taliglucerase alfa. Efficacy was determined by evaluation of platelet counts, hemoglobin levels, and spleen and liver volumes for clinical deterioration. The control for this study was each patient’s previous historical clinical and stability laboratory measurements. At completion of the 9-month study, patients were eligible to enter an open-label extension study, PB06-003, with taliglucerase alfa given every 2 weeks at the same dose as in study PB-06-002. This is an interim report for the 15 adult patients who have completed 24 total months of treatment. Following 24 months’ treatment with taliglucerase alfa, efficacy parameters of spleen volume, liver volume, platelet counts, hemoglobin concentration, and chitotriosidase activity were maintained or improved in these patients following switchover to taliglucerase alfa. None of the patients met the criteria for clinically relevant deteriorations as specified by the study protocol. All treatment-related adverse events were mild or moderate in severity and transient in nature.

A clinical association has been reported between type 1 Gaucher's disease, which is caused by a glucocerebrosidase deficiency owing to mutations in the glucocerebrosidase gene (GBA), and parkinsonism. We examined whether mutations in the GBA gene are relevant to idiopathic Parkinson's disease.A clinic-based case series of 99 Ashkenazi patients with idiopathic Parkinson's disease, 74 Ashkenazi patients with Alzheimer's disease, and 1543 healthy Ashkenazi Jews who underwent testing to identify heterozygosity for certain recessive diseases were screened for the six GBA mutations (N370S, L444P, 84GG, IVS+1, V394L, and R496H) that are most common among Ashkenazi Jews.Thirty-one patients with Parkinson's disease (31.3 percent; 95 percent confidence interval, 22.2 to 40.4 percent) had one or two mutant GBA alleles: 23 were heterozygous for N370S, 4 were heterozygous for 84GG, 3 were homozygous for N370S, and 1 was heterozygous for R496H. Among the 74 patients with Alzheimer's disease, 3 were identified as carriers of Gaucher's disease (4.1 percent; 95 percent confidence interval, 0.0 to 8.5 percent): 2 were heterozygous for N370S, and 1 was heterozygous for 84GG. Ninety-five carriers of Gaucher's disease were identified among the 1543 control subjects (6.2 percent; 95 percent confidence interval, 5.0 to 7.4 percent): 92 were heterozygous for N370S, and 3 were heterozygous for 84GG. Patients with Parkinson's disease had significantly greater odds of being carriers of Gaucher's disease than did patients with Alzheimer's disease (odds ratio, 10.8; 95 percent confidence interval, 3.0 to 46.6; P0.001) or control subjects (odds ratio, 7.0; 95 percent confidence interval, 4.2 to 11.4; P0.001). Among the patients with Parkinson's disease, patients who were carriers of Gaucher's disease were younger than those who were not carriers (mean [+/-SD] age at onset, 60.0+/-14.2 years vs. 64.2+/-11.7 years; P=0.04).Our results suggest that heterozygosity for a GBA mutation may predispose Ashkenazi Jews to Parkinson's disease.

Among the phenotypes associated with Gaucher disease, the deficiency of glucocerebrosidase, are rare patients with early onset, treatment-refractory parkinsonism. Sequencing of glucocerebrosidase in 17 such patients revealed 12 different genotypes. Fourteen patients had the common "non-neuronopathic" N370S mutation, including five N370S homozygotes. While brain glucosylsphingosine levels were not elevated, Lewy bodies were seen in the four brains available for study. The shared clinical and neuropathologic findings in this subgroup suggest that the deficiency in glucocerebrosidase may contribute to a vulnerability to parkinsonism.

Type 1 Gaucher disease is considered the non-neuronopathic form of this autosomal recessively inherited lysosomal storage disease. We report the simultaneous occurrence of Gaucher disease with parkinsonian in four adult patients. The patients had a relatively early onset of parkinsonian manifestations, and their disease was rapidly progressive and refractory to therapy. Each had a different Gaucher genotype, although four alleles carried the common N370S mutation. No mutations were identified in the genes for parkin or alpha-synuclein. The concurrence of these two phenotypes, both in this series of patients and in others in the literature, suggests a shared pathway, modifier, or other genetic etiology.

Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-risk) myelodysplastic syndromes (MDS). Lenalidomide is effective in lower-risk (LR) MDS, with or without 5q-, in HR-MDS and in acute leukemia. Many patients remain resistant to a single agent. A potential synergistic effect of both agents has been shown [Sekeres M et al, Am J Hemat 2010; Blood 2012]. Thus, the MDS Israel group has designed a phase II clinical trial (NIH trial #: TASMC-10-MM-0437-09-CTIL). Protocol The ViLen-01 protocol consists of 3 phases. The induction phase includes 6 monthly cycles of SC azacitidine (Aza), 75 mg/m daily, days 1-5, and PO lenalidomide (Len) 10 mg daily, days 6-21, followed by a 7-day (days 22-28) respite. The consolidation consists of 6 monthly cycles of Aza only for 5 days each, followed by 12 months of maintenance with Len only. Response is evaluated by the IWG criteria [Cheson B et al, Blood 2006]. Results As of July 2013, 7 medical centers have enrolled 18 patients. Patients had been diagnosed with either HR-MDS, or LR-MDS with transfusion-dependence, erythropoietin resistance and poor cytogenetics. Adverse events (AE) were as expected in these elderly HR-MDS patients. The common AEs were grade IV transient cytopenias, requiring dose modification in 15 patients. Only 2 patients stopped the protocol due to AE. Thirteen patients completed the induction, 8 continued to consolidation, and 5 patients continued to maintenance. Eight of the 18 enrolled patients (44%, 8 of the 13, 61.5%) who had completed the induction, achieved CR. Three of the 8 patients in CR also attained cytogenetic response. The other 5 had normal karyotype on study initiation. Five other patients obtained erythroid response and became transfusion-free, and another patient achieved platelet response, for a total of 14 (78%) responders. It is still too early to evaluate response duration and survival. One patient is in early induction, and 4 are still being treated. The others have either died or have discontinued for various reasons (patient refusal, progressive disease, transplant). Conclusions These preliminary data in a small group of patients with HR-MDS and expected poor prognosis, demonstrate a high response rate and a reasonable safety profile. The study is ongoing. If these results are confirmed in randomized trials, it may set new standards for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.

Dear Editor, Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disease (HSC), characterized by intravascular hemolysis [1] due to inactivating mutation of the X-linked PIG-A gene in an HSC; the gene product is essential for the synthesis of glycosylphosphatidylinositol (GPI) anchor molecules [2]. Intravascular hemolysis is a major cause of anemia in PNH. Two surface proteins, CD55 and CD59, which regulate complement activation on the cell surface are GPI-linked [3], and their deficiency explains the hypersusceptibility of PNH red blood cells (RBC) to complementmediated lysis, intravascular hemolysis, and release of free hemoglobin (Hb). Hb has a vasculotoxic potential, directly impairing endothelial function and generating inflammatory and oxidative stress [4]. Cell-free Hb disintegrates into heme and globin, and the iron from heme catalyzes the formation of reactive oxygen species (ROS) [5] causing damage to various components of the cell. Flow cytometry analyses of RBC, platelets, and polymorphonuclear cells from patients with PNH disclosed a significant increase in ROS, while reduced glutathione was decreased. Oxidative stress was more profound in cells derived from the pathological clone with a CD55–CD59 phenotype. Increased membrane lipid peroxidation was also documented in PNH RBC [6]. Consequently, there is evidence for increased oxidative stress in PNH, which might play a significant role in the pathophysiology of the disease. Indeed, in vitro treatment of PNH-RBC with antioxidants decreased their hemolysis [6]. Therefore, there is a rationale for treatment with antioxidants in order to reduce the oxidative stress and improve its clinical manifestations in PNH patients. One antioxidant is fermented papaya preparation (FPP), a natural health food product obtained by yeast biofermentation of carica papaya [7], which decreases oxidative stress both in vitro and in vivo [8].