Iron Overload Diminishes the Effectiveness of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4071-4071
Author(s):  
Patrick B Walter ◽  
Paul R Harmatz ◽  
Annie Higa ◽  
David Killilea ◽  
Nancy Sweeters ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Iron Overload ◽  
Board Of Directors ◽  
Innate Immune Response ◽  
Research Funding ◽  
Innate Immune ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Fluorescent Intensity

Abstract Abstract 4071 Poster Board III-1006 Introduction Infection is the second most common cause of death in thalassemia. The innate immune system provides a first line of defense against infection and specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) are important for transducing the signal for bacterial Lipopolysaccharide (LPS), resulting not only in cytokine production, but also in the control of extracellular iron levels through production of neutrophil gelatinase associated Lipocalin (NGAL). However, the exact role that NGAL plays and the expression level of PRRs are unknown in thalassemia. Thus, the goal in these studies is to investigate the relationship of iron overload to the innate immune cell expression of PRRs and NGAL in thalassemia. Patients and Methods Fifteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox (an oral iron chelator) and deferoxamine were enrolled (Novartis sponsored CICL670AUS24T). Fasting blood samples were obtained i) at baseline after a 72 hr washout of chelator, and ii) at 6 and 12 months on study. Five healthy controls (13 - 18 yrs old) were also enrolled. Fresh monocytes were isolated using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes were verified by flow cytometry. The expression of TLR4, also examined by flow cytometry is reported as the mean fluorescent intensity (MFI). In patients with thalassemia, liver iron concentration (LIC) was analyzed by biomagnetic susceptibility (“SQUID”, Ferritometer®). The plasma levels of NGAL were analyzed by ELISA. Results At baseline the expression of monocyte TLR4 (mean 18.8 ± 3.5 MFI) was reduced 30% compared to the healthy controls (mean 26.9 ± 7.6 MFI, p<0.05). The expression of TLR4 over the follow-up period of 52 weeks in patients receiving intensive combination chelator therapy significantly increased 27% / year (7 MFI / year, p=0.005). Interestingly the expression of monocyte TLR4 was negatively correlated with LIC (r=-0.6, p=0.04). Finally, thalassemia patients at baseline have significantly higher levels of NGAL (80 ± 20 ng/ml) compared to controls (42 ± 15 ng/ml, p=0.01). Conclusions These preliminary studies support the hypothesis that iron burden has a negative impact on the innate immune response in thalassemia as demonstrated by the decreased expression of TLR4. After intensive chelation, the levels of TLR4 increased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. Finally, the iron transport protein NGAL is significantly elevated in thalassemia possibly acting to prevent essential iron uptake by pathogenic bacteria. Disclosures: Harmatz: Novartis: Research Funding; Apotex : Membership on an entity's Board of Directors or advisory committees; Ferrokin: Membership on an entity's Board of Directors or advisory committees. Vichinsky:Novartis: Consultancy, Research Funding.

scholarly journals Conversion from MRD Positive to Negative Status in AML Patients in CR1 after Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Arjan van de Loosdrecht ◽  
Janine van Elssen ◽  
Bjørn Tore Gjertsen ◽  
Eva Maria Wagner ◽  
Tobias Holderried ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Dendritic Cell ◽  
Complete Remission ◽  
Immune Responses ◽  
Board Of Directors ◽  
Research Funding ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Advisory Committees

Background. Persistence of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) remains a poor prognostic factor and unmet medical need. The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown in a phase I study to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In the current phase II study (Clintrials.gov: NCT03697707) we show the capability of DCP-001 to convert MRD positive patients to negative, leading to deeper remissions. Additionally, it is shown that DCP-001 induces immune responses, also specifically against tumor associated antigens known to be present in DCP-001 and relevant for AML. Methods. The current trial aims to enroll up to 20 AML -patients, ineligible for HSCT, who are in in first complete remission (CR1) but who are still MRD positive. MRD is assessed in the bone marrow through flow cytometry and/or qPCR (eg NPM1). Patients receive a primary vaccination regimen of 4 times 25.106or 50.106cells per vaccination, biweekly, followed by two booster vaccinations (10.106cells/vaccination) at week 14 and 18 after start of treatment. Primary endpoints of this trial are the safety and tolerability of the two vaccination schedules and the effect of vaccination on the MRD status. Additionally, cellular and humoral immune response induced by DCP-001 are evaluated in peripheral blood using several assay methods, including flow cytometry and IFN-ϒ ELISpot against known TAA's such as WT-1, RHAMM and PRAME. Results. Up to 15 July 2020, ten patients (age 41-76; 5 male, 5 female) have been enrolled and dosed within the study, completing the first dose cohort of 25.106cells/vaccination. All vaccinations were well tolerated and adverse events to the vaccine were limited to local injection site reactions such as redness, swelling and warmth (maximum grade 2). Three of the ten patient relapsed before the vaccination schedule was completed. Four patients could be evaluated for MRD; Two patients became MRD negative at the first timepoint after the initial vaccinations (week 14), and remained negative until end of active FU (week 32), two other patients remained in CR, but with MRD positivity. For the remaining three patients, to date, no MRD outcome is available yet but patients remain in CR (see swimmers plot for overview, Figure 1). Evaluation of the immune response before, during and after DCP-001 vaccination has only be performed in a small subset of three patients thus far. Of these patients one showed a clinical response becoming MRD negative after vaccination. In this patient we observed an increase in tumor specific functional T-cells assessed by IFNγ ELISPOT, either as a recall or primary response, as shown by the response observed to WT-1 (see for example Figure 2). These tumor associated antigens are known to be expressed by DCP-001 and included WT1, PRAME and RHAMM. Induction of specific memory CD8 and CD4 cells could be observed upon vaccination which might be related to the clinical response. Conclusion/discussion.Preliminary data from this ongoing study confirms that vaccination with DCP-001 is able to generate a tumor-specific immune response and may lead to potential tumor control. Two patients were actually converted from being MRD positive at start of vaccination to MRD negative during the study. These patients continue to be in complete remission for at least a year after vaccination. This study continues to enroll patients at a higher vaccine dose of 50.106cells per vaccination and additional data on induced immune responses and MRD status will be shown. Disclosures van de Loosdrecht: novartis: Honoraria; celgene: Honoraria. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Other: Travel grand; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria. Rovers:DCprime: Current Employment.

Role of Hypoxia in the Progression and Dissemination of Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 421-421
Author(s):  
Abdel Kareem Azab ◽  
Phong Quang ◽  
Feda Azab ◽  
Aldo M. Roccaro ◽  
Antonio Sacco ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Board Of Directors ◽  
Stromal Cells ◽  
Research Funding ◽  
Phase Cell ◽  
Advisory Committees ◽  
Fluorescent Intensity ◽  
Hypoxic Conditions

Abstract Abstract 421 INTRODUCTION: Multiple myeloma (MM) is characterized by the disseminated involvement of the bone-marrow (BM), and its progression involves a continuous circulation of the MM cells in the peripheral blood and homing back to the BM. Several reports have described the mechanism involved in homing of MM cells to the BM. However, the driving force to metastasize from one site of the BM to another is not yet understood. Hypoxia (oxygen deprivation) was associated with poor patient prognosis in solid tumors, and several studies have shown that BM has a hypoxic nature. We hypothesize that the hypoxic nature of the BM and the rapid development of MM may cause induction of hypoxia in the tumor microenvironment, induce stress in the MM cells, and drive them to disseminate to new BM niches with normal oxygen levels (normoxia). METHODS AND RESULTS: First we have tested the level of oxygenation of MM cells and cells from its BM microenvironment by injection of pimonidazole (PIM) to mice with MM and determined the levels of PIM binding in MM cells and stromal cells in the microenvironment by flow cytometry. The whole cells population in the BM was hypoxic, while the MM cells were more hypoxic compared to cells in the microenvironment. We have mimicked these results in vitro by incubation of MM cells (cell lines and patients samples) in hypoxic conditions (0.5% oxygen, for 24 hrs). Induction of hypoxia was also verified by detection of increased binding of PIM by flow cytometry, and increased levels of HIF1 and HIF2 in MM cells by immunoblotting. MTT assay showed that hypoxia significantly decreased (40%) the survival of MM cells. Immunoblotting showed a downregulation of proliferative signaling pathway, including PI3K, AKT, mTOR and ERK; and induction of stress pathways including MKK-3 and 6, and p38. Apoptosis was not detected by flow cytometry after 24 hrs of hypoxic conditions. These results were confirmed by immunoblotting, which showed no change in apoptosis related proteins including caspases 3 and 7, Bcl-2, Bcl-xL and Mcl-1. However, hypoxia induced G1-phase cell cycle arrest (increase of 20% in G1)., These results were confirmed by immunoblotting showing downregulation of proteins associated with G1 to S phase transition including cyclins D1, D2, D3 and E1, and pRb; and upregulation of cell cycle inhibitor p27. Testing the effect of hypoxia on the adhesion properties of MM cells to BM stromal cells (BMSCs) revealed that hypoxic MM cells were 50% less adherent to BMSCs compared to normoxic MM cells. Also, hypoxic BMSCs induced 30% less adhesion of MM cells compared to normoxic BMSCs. Mechanistically, immunoblotting showed a significant decrease in the expression of cadherins in both hypoxic MM cells and hypoxic BMSCs. The chemokine stromal-cell derived factor-1-alpha (SDF1) is known to increase adhesive properties of MM cells, and to induce MM retention in the BM. Testing the levels of SDF1 revealed that hypoxia decreased SDF1 secretion (40%) from BMSCs. As a result, media from hypoxic BMSCs induce significantly decreased MM cell chemotaxis (20%) compared to media from normoxic BMSCs. These findings suggest that hypoxic BM will retain less MM cells in the BM and allow more egression. Comparison of the ability of hypoxic and normoxic MM cells to migrate towards normoxic BMSCs or SDF1 revealed that hypoxic MM cells had increased (250% and 350%, respectively) chemotactic properties compared to normoxic MM cells. These findings correlated with the increased expression of CXCR4 on hypoxic MM cells (mean fluorescent intensity shifts: Isotype=90, normoxic = 520, hypoxic = 1100). These results suggest that hypoxic MM cells will home to normoxic BM niches more efficiently than normoxic MM cells. Finally, testing the recovery of the hypoxic MM cells after incubation in normoxic conditions showed that the expression of CXCR4 was completely downregulated to levels found in normoxic cells after 6 hrs of exposure to normoxia. Moreover, incubation of hypoxic MM cells in normoxic BMSCs- media or SDF1 restored their expression of cadherins and their ability to adhere to BMSCs. CONCLUSION: In conclusion, we have showed that hypoxia inhibited the proliferation of MM cells and decreased their adhesion to BMSCs, as a first step of egress and metastasize to new normoxic BM niches. Disclosures: Anderson: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Genomic and Transcriptomic Differences of Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T) and Myelodysplastic Syndrome with Ring Sideroblasts (MDS-RS)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Guillermo Montalban Bravo ◽  
Rashmi Kanagal-Shamanna ◽  
Faezeh Darbaniyan ◽  
Irene Ganan-Gomez ◽  
Koji Sasaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasm ◽  
Enrichment Analysis ◽  
Cytokine Signaling ◽  
Healthy Controls ◽  
Kinase Signaling ◽  
Advisory Committees ◽  
Ring Sideroblasts

INTRODUCTION: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematological disorder characterized by anemia, bone marrow dysplasia with ring sideroblasts and persistent thrombocytosis, and high frequency of SF3B1 and JAK2 mutations. Despite clinical, histological and molecular similarities with MDS with ring sideroblasts (MDS-RS), the clinical outcomes of these entities are diverse. To date, there is no data evaluating specific functional pathways which might explain phenotypic and clinical differences beyond diverse frequencies of JAK2 mutation. METHODS: We evaluated a total of 24 patients (pts) with MDS/MPN-RS-T and 27 pts with MDS-RS. Diagnosis was based on WHO 2017 criteria and confirmed by two independent hematopathologists. Whole bone marrow DNA was subject to 81 gene targeted next-generation sequencing (NGS) analysis. CD34+ cells from bone marrow samples of 4 pts with MDS/MPN-RS-T, 7 pts with MDS-RS and 17 healthy individuals obtained from AllCells (Emeryville, CA) were isolated using the CD34 MicroBead Kit and RNA was isolated using the PicoPure RNA isolation kit. Fastq files were mapped to the human genome (build GRCh38) in TopHat2 using the default options. Differential gene expression analysis was conducted using DESeq2 in R version 3.6.2. Pathway enrichment analysis was performed using gene set enrichment analysis, with the fgsea library in R. RESULTS: Patients with MDS/MPN-RS-T had higher median bone marrow ring sideroblast percentage (47% vs 32%, p=0.04) and absolute neutrophil count (4.34x109/L vs 2.99x109/L, p=0.001). Frequency of identified mutations and their VAFs compared to MDS-RS are shown in Figure 1A. The median number of mutations was higher in MDS/MPN-RS-T than in MDS-RS (3 vs 2, p&lt;0.001). SF3B1 mutations were the most frequent in both entities (MDS/MPN-RS-T: 92%, MDS-RS: 82%), had similar median VAF (34% vs 32%, p=0.619), and involved the hot spot codon K700E in 64% and 43% of MDS-RS and MDS/MPN-RS-T (p=0.227), respectively. As expected, 58% of pts with MDS/MPN-RS-T had JAK2 V617F mutations but were also more likely to have mutations in kinase signaling genes (NF1, SETBP1, CBL, CBLB, FLT3 TKD, MPL) compared to MDS-RS (29% vs 4%, p=0.019). Four (40%) of JAK2 negative MDS/MPN-RS-T had mutations in kinase signaling genes. There were no differences in frequency of TET2 mutations between both entities. However, there was a trend for the median VAF of TET2 mutations in MDS/MPN-RS-T to be lower than in MDS-RS (1.5% vs 21.1%, p=0.177) suggesting a likely subclonal nature of these mutations compared to MDS-RS in which they appeared as dominant events. MDS/MPN-RS-T showed distinct transcriptomic profile compared to both healthy controls and MDS-RS. Compared to healthy controls, a total of 2 pathways were significantly upregulated and 58 were downregulated in MDS/MPN-RS-T while 5 pathways were upregulated and 69 were downregulated in MDS-RS. Compared to MDS-RS, a total of 29 pathways were significantly upregulated and 26 were downregulated in MDS/MPN-RS-T. The most significantly upregulated pathways in MDS/MPN-RS-T included genes involved in platelet activation and aggregation, cytokine signaling, and signaling through GPC receptors (Figure 1C). Compared to both healthy control and MDS-RS, MDS/MPN-RS-T was characterized by downregulation of genes involved in DNA damage response, regulation of apoptosis, telomere maintenance and RNA synthesis (Figure 1D). MDS-RS was characterized by downregulation of genes involved in signaling by GPC receptors and MAPK signaling, mRNA splicing, cytokine signaling and signaling through interleukins compared to both control and MDS/MPN-RS-T (Figure 1C). CONCLUSIONS: MDS/MPN-RS-T is characterized by co-dominance of SF3B1 and JAK2 mutations and presence of minor kinase signaling mutations not observed in MDS-RS. Upregulation of cytokine and interleukin signaling mediated through GPC receptors, and downregulation of genes involved in apoptosis and DNA damage are unique transcriptomic features of MDS/MPN-RS-T likely driven by genotype. These unique genomic and transcriptomic characteristics of MDS/MPN-RS-T supports the classification of MDS/MPN-RS-T based on genomic features beyond presence of SF3B1 mutation, and might represent potential therapeutic avenues for this rare disease. Figure Disclosures Sasaki: Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Kantarjian:Sanofi: Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BioAscend: Honoraria; Novartis: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Ascentage: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy.

A Phase I/II, Open-Label, Dose-Escalation Trial of Once-Daily Oral Chelator Deferasirox to Treat Iron Overload in HFE-Related Hereditary Hemochromatosis: Final Results of the Core Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1514-1514 ◽  
Author(s):  
Pradyumna D. Phatak ◽  
Pierre Brissot ◽  
Herbert Bonkovsky ◽  
Mark Wurster ◽  
Lawrie Powell ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Hereditary Hemochromatosis ◽  
Advisory Committees ◽  
The Core ◽  
Upper Limit ◽  
Dose Dependent

Abstract Abstract 1514 Poster Board I-537 Background and aims Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by progressive iron overload through increased intestinal absorption. Phlebotomy treatment is the standard of care, but compliance is variable and some patients are poor candidates due to underlying medical disorders and/or poor venous access. An oral iron chelator such as deferasirox (Exjade®) may provide an alternative treatment option for HH patients. Methods This is an inter-patient dose-escalation study of deferasirox (5, 10, 15 and 20 mg/kg) administered daily for 24 weeks to C282Y HFE homozygous HH patients with a pre-treatment serum ferritin (SF) value of 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis. A 6-month extension of this trial has recently been completed. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include change in SF, time to SF normalization (<100 ng/mL), longitudinal course of SF, and pharmacokinetics of deferasirox. Results 49 patients were enrolled and 48 patients were treated (33 men, 16 women; mean age 50.6 years; mean of 3.1 years since HH diagnosis) with deferasirox 5 (n=11), 10 (n=15) or 15 mg/kg/day (n=23) for at least 24 weeks. 37 (75.5%) patients completed the study (10 [90.9%], 11 [73.3%]; 16 [69.6%] patients in the 5, 10 and 15 mg/kg/day groups, respectively. The most common reasons for discontinuation were AEs in 3 (20.0%) patients and 4 (17.4%) patients in the 10 and 15 mg/kg/day groups, respectively. Bayesian analysis and medical review were performed between dose escalations. Meaningful reductions in SF were observed across the first three dose groups (median decrease -31.1%, -52.8% and -55.4% in the 3 groups respectively), and escalation to 20 mg/kg/day was not undertaken. Time course of the SF decline was dose-dependent (Figure). AEs in the core were dose dependent and consistent with the known safety profile of deferasirox. The most common drug-related AEs (≥10% in all patients) reported were diarrhea in 1 (9%), 4 (27%) and 9 (39%) patients, nausea in 0 (0%), 2 (13%) and 4 (17%) patients and abdominal pain in 0 (0%), 2 (13%), 3 (13%) patients in the 5, 10 and 15 mg/kg/day groups, respectively. One patient had ALT >5X upper limit of normal, and 11 patients had serum creatinine ≥33% over baseline and upper limit of normal on two consecutive occasions. All resolved with dose cessation or modification. Conclusions The results from the CORE trial suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden in HH patients. Based on the safety profile, only the 5 and 10 mg/kg/day doses are being considered for further study in this population. The results of the 24 week extension phase will be available at the time of the meeting. Larger studies are required to define the appropriate treatment regimen in HH. Disclosures Phatak: Novartis: Honoraria, Speakers Bureau. Brissot:Novartis: Honoraria, Research Funding. Bonkovsky:Boehringer-Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinuvel: Consultancy; Lundbeck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Roche: Research Funding; Vertex: Research Funding. Niederau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adams:Novartis: Honoraria. Griffel:Novartis: Employment, Equity Ownership. Lynch:Novartis Pharmaceuticals: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment.

Randomized Phase II Study Evaluating the Efficacy and Safety of Deferasirox in Non-Transfusion-Dependent Thalassemia Patients with Iron Overload.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5111-5111 ◽  
Author(s):  
Ali Taher ◽  
John B. Porter ◽  
Antonis Kattamis ◽  
Vip Viprakasit ◽  
Tomasz Lawniczek ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Thalassemia Intermedia ◽  
Advisory Committees

Abstract Abstract 5111 Background Clinically mild forms of thalassemia exist that, unlike β-thalassemia major, require no or only infrequent transfusions (eg. β-thalassemia intermedia, HbH disease). However, due to increased gastrointestinal iron absorption secondary to ineffective erythropoiesis these patients may still develop iron overload. For example, thalassemia intermedia patients (n=74) within a cross-sectional study had a mean serum ferritin (SF) of 1023 ng/mL (range 15–4140) and a mean liver iron concentration (LIC) of 9 mg Fe/g dw (range 0.5–32.1) at baseline despite most being transfusion-naïve (n=20) or rarely transfused (n=45), and only nine receiving regular transfusions (2–4 times/yr) (Taher et al. ITIFPaP: 13th International TIF Conference for Thalassaemia Patients & Parents, October 8–11 2008, Singapore, poster number MON04). Non-transfusional iron overload leads to the same serious clinical sequelae as transfusional iron overload, including liver, cardiac and endocrine dysfunctions. As patients with non-transfusional iron overload are not candidates for phlebotomy due to their underlying anemia, chelation therapy is the only available option for decreasing their iron burden. However, there is currently limited data available on the use of chelation in this population. The once-daily oral iron chelator deferasirox (Exjade®) is currently approved for the treatment of iron overload in patients with transfusion-dependent anemia. This prospective, randomized, double-blind, placebo-controlled Phase II ‘THALASSA’ study will evaluate the efficacy and safety of deferasirox in patients with non-transfusion-dependent thalassemia. Methods Non-transfusion-dependent thalassemia patients aged ≥10 yrs will be randomized 2:1:2:1 to starting doses of deferasirox/placebo 5 mg/kg/day/ deferasirox/placebo 10 mg/kg/day over a planned 12-month treatment period. Doses can be doubled after 6 months should patients require a higher dose, which will be determined after 6 months of treatment. All patients are required to have a baseline LIC of ≥5 mg Fe/g dw, as measured by R2 magnetic resonance imaging, and SF levels of >300 ng/mL. Patients will be excluded if they have: anticipated regular transfusions during the study (sporadic transfusions, such as in cases of infection, are allowed); any transfusion within 6 months prior to study start, chelation within 1 month prior to study start; HbS variants of thalassemia; impaired renal and liver function. Primary efficacy endpoint is absolute change from baseline in LIC at 12 months; secondary efficacy endpoints include change from baseline in LIC after 6 months and in SF after 6 and 12 months, as well as change in hematological and iron metabolism parameters (eg hemoglobin, transferrin saturation). Safety assessments include adverse event and laboratory parameter monitoring. 156 patients are planned for inclusion. Results As of 3 August 2009, 18 sites had been activated. Sites currently activated are in Thailand (n=5), Turkey (n=4), Italy (n=3), Malaysia (n=2), UK (n=2) Lebanon (n=1). Fifty-seven patients have been randomized to either deferasirox or placebo and their demographic data are shown in Table 1. Conclusions Similar to transfusion-dependent thalassemia patients, non- transfusion-dependent thalassemia patients also develop iron overload. This ongoing study will generate prospective efficacy and safety data for the use of deferasirox in non-transfusion-dependent thalassemia patients with iron overload. To prevent long term complications due to iron overload, it is important to assess iron chelation in this patient population as they are not candidates for phlebotomy due to the underlying anemia. Disclosures Taher: Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Pereno:Novartis Pharma AG: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

Combined Chelation Therapy with Deferasirox and Deferoxamine In Transfusion-Dependent Thalassemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4269-4269 ◽  
Author(s):  
Ashutosh Lal ◽  
Nancy Sweeters ◽  
Vivian Ng ◽  
Drucilla Foote ◽  
Patricia Evans ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Chelation Therapy ◽  
Liver Weight ◽  
Myocardial Iron ◽  
Advisory Committees ◽  
Single Drug ◽  
Median Plasma ◽  
Group B

Abstract Abstract 4269 Therapeutic regimens that combine two iron chelators may enhance chelation efficiency by improving access to different tissue iron stores and control of the toxic labile iron pool. The combination of two chelators can reduce toxicity through averting the need for high doses of a single drug, but it is essential to establish the safety such regimens. We therefore explored the combined use of deferasirox (DSX) and deferoxamine (DFO) in patients with transfusion-dependent thalassemia who had failed standard chelation therapy with single drug. Patients were eligible if the liver iron concentration (LIC) >15 mg/g dry liver-weight or if iron-induced end organ injury was present. Subjects were monitored for hepatic and renal toxicity, visual or auditory changes, and the development of new complications from iron overload. The ability of the combined therapy to control systemic iron burden (serum ferritin and LIC) and myocardial iron overload (MRI T2*) was evaluated. We also measured changes in plasma levels of non-transferrin bound iron (NTBI) and labile plasma iron (LPI). Fifteen subjects were enrolled in 3 groups: adults with LIC <15 mg/g dry liver-weight (group A), adults with LIC >15 mg/g (group B), and children 8–18 years with LIC >5 mg/g (group C). The duration of therapy was 52 weeks. DSX (20-30 mg/Kg) was administered daily and DFO (35-50 mg/Kg/infusion) was infused on 3–7 days/week (as 8–12 hour infusion) based upon the degree of iron overload present at baseline. At the initiation of the study, the mean daily dose of DFO was 16, 33, and 17 mg/Kg/day and mean DSX dose was 21, 25 and 22 mg/Kg/day for groups A, B and C, respectively. At the conclusion of the trial, the median LIC declined by 48% from 10.8 mg/g (3.9-34.8 mg/g) to 5.7 mg/g (1.0-24.0 mg/g, p=0.003). The median ferritin fell by 43% from 2030 ng/mL (1000-5230 ng/mL) to 1150 ng/mL (421-5260 ng/mL, p=0.008). Myocardial iron in the 3 subjects who had T2* <20 msec at study entry (range 6.5–19.5 msec at week 0) showed an average improvement of +2.43 msec following treatment (range 8.8–21.3 msec at week 52, p=0.027). All 3 subjects with left ventricular ejection fraction below 60% at baseline (47.5-58.1%) showed improvement at end of study (60.6-64.4%). There was progressive decline in median plasma NTBI level during the study from 3.26 μM (1.79-5.79 μM) at baseline to 2.38 μM (1.59-3.08 μM) at 12 months (p=0.008). DSX produced immediate and significant decline in plasma NTBI when administered during infusion of DFO. The median plasma NTBI measured on DFO alone was 2.46 μM (0.92-5.90 μM), which decreased to 1.96 μM (0-3.50 μM) following administration of the dose of DSX (p<0.001). A sustained control of the LPI fraction was also demonstrated throughout the study period. At baseline the median LPI was 0.87 μM (0-2.43 μM) which decreased to 0.05 μM (0-1.20 μM) during the study period (p=0.004). No significant toxicity or unusual adverse events were observed with combined chelation therapy in this group of high-risk patients with thalassemia. Elevation of serum creatinine or ALT was not observed in any subject. One subject from group B died at 9 weeks from start of trial from sepsis. One subject interrupted DSX therapy because of abdominal pain. In all other cases the treatment was well tolerated and no dose adjustment or suspension of therapy was required on account of toxicity. Protocol-mandated modification of treatment (temporary cessation of DSX or DFO) occurred in three subjects owing to a marked fall in serum ferritin and LIC. These results suggest that simultaneous administration DSX and DFO is well tolerated and has low potential for toxicity. Combined chelation therapy appears to be effective in rapidly reducing systemic iron burden, lowering myocardial iron, and controlling plasma NTBI and LPI in patients at risk of developing end-organ damage. Disclosures: Harmatz: Ferrokin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vichinsky:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Deregulation of TNFRSF18 (GITR) Through Promoter CpG Island Methylation Induces Tumor Proliferation in Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2424-2424
Author(s):  
Yang Liu ◽  
Yong Zhang ◽  
Phong Quang ◽  
Hai T Ngo ◽  
Feda Azab ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Cpg Island ◽  
Advisory Committees ◽  
Brdu Assay

Abstract Abstract 2424 Introduction Tumor necrosis factor receptor super families (TNFRSFs) play an important role in activation of lymphocyte and cell apoptosis. However the function of TNFRSFs in multiple myeloma (MM) remains unknown. Loss of function mutation of Fas antigen (TNFRSF6) was identified in MM cells, thus suggesting the possible role of TNFRSFs in regulating MM pathogenesis. We therefore investigated the epigenetic mechanisms that may mediate inactivation of TNFRSFs and its functional role in MM. Methods Dchip software was utilized for analyzing gene expression dataset. DNA was extracted from both primary CD138+ MM plasma cells and MM cell lines using blood & tissue DNA isolation kit (Qiagen, Inc.). Expression of GITR in primary CD138+ plasma cells was detected by Imunohistochemistry (IHC) DNA methylation was analyzed by methylated DNA immunoprecipitation (Medip) assay and bisulfate sequencing. 5'azacytidine was used to demethylate genomic DNA. Gene expression was detected by qRT-PCR and confirmed at the protein level by flow cytometry and western-blot. Over-expression of GITR was obtained in MM1.S cells by using GITR recombinant plasmid and electroporation. Apoptosis was determined using Annexin/PI staining and flow cytometry analysis. Activation of apoptotic signaling was studied by western blot. Cell survival and proliferation were analyzed by MTT and BrdU assay, respectively. Recombinant GITR-lentivirus was obtained from the supernatant of culture medium after 72 hours transfection in 293 cells. GFP positive MM cells were sorted and analyzed by flow cytometry. In vivo effect of GITR on MM tumor growth was determined by injection of GITR over-expressing MM cells in null mice. Mice skull, femur and vertebrae were isolated after 4 weeks injection. Anti-human CD138+ mAb microbead was used to detect MM cells extracted from mice tissue by flow cytometry. Results Gene-expression profiling showed down-regulation of TNFRSFs, including TNFRSF11A, TNFRSF11B, TNFRSF8, TNFRSF10C, TNFRSF9, TNFRSF21, TNFRSF1B, TNFRSF1A and TNFRSF18, compared to normal plasma cells. Moreover, Our IHC results also showed that GITR expression was positive in primary CD138+ plasma cells from 9 normal bone marrow, but negative in 9 MM samples. Importantly, we found that low GITR expression significantly correlated with MM progression. Indeed, GITR gene levels were lower in smoldering and active MM patients compared to MGUS patients and normal donors. Promoter CpG island (CGI) methylation of GITR was indentified in 5 out of 7 MM primary bone marrow (BM)-derived CD138+ cells but not in normal BM-derived plasma cells. Bisulfate sequencing and Medip assay showed that methylation of GITR was significantly associated with GITR expression in 5 MM cell lines, including MM1.S, OPM1, U266, RPMI and INA6. Promoter CGI of GITR was highly methylated leading to complete silencing of GITR in MM1.S cell line. GITR expression was significantly up-regulated in MM cells upon treatment with the 5'azacytidine. MTT and BrdU assay revealed that the proliferation and survival of MM1.S cells was disrupted in the GITR over-expressing MM1.S cells, notably with inhibition of cell proliferation compared to control vector infected cells. Moreover induction of cytotoxicity in GITR over-expressing cells was confirmed by using GFP competition assay. GITR-induced apoptosis was supported by induction of caspase 8 and 3 cleavage. The inhibition of human CD138+ plasma cell growth in the bone marrow of SCID mice using a disseminated MM xenograft model was observed in the experimental group injected with GITR expressing cells compared to the control group after 4 weeks injection. Conclusion Our findings uncovered a novel epigenetic mechanism contributing to MM pathogenesis, showing the role of GITR methylation as a key regulator of MM cell survival. Disclosures: Roccaro: Roche:. Ghobrial:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1016-1016 ◽  
Author(s):  
John Porter ◽  
Ali T Taher ◽  
Yesim Aydinok ◽  
Maria D Cappellini ◽  
Antonis Kattamis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Iron Removal ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Significant Difference ◽  
Liver Iron Overload ◽  
The Impact

Abstract Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al., 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC <7, 7–≤15 and >15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p-values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC <7 mg/g), 38.0 ±3.4 (LIC 7–≤15 mg/g), and 37.6 ±3.1 (LIC >15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC <7 mg/g. After 36 months, a significant mean decrease from BL in LIC of -7.6 ±4.6 mg/g (p = 0.0049) and -16.8 ±14.0 mg/g (p <0.001) was observed in patients with LIC ≤15 and >15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p=0.0016) and 46% (7.3 ±7.3 ms, p<0.001), respectively. Patients with BL LIC ≤15 normalized mT2* in 24 months (Mean, 20.0 ±6.0 ms) versus 36 months for patients with BL LIC >15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC <7 mg/g (24% increase; mean abs. change, 3.5 ±2.3 ms), LIC 7–≤15 mg/g (19% increase; 3.4 ±5.2 ms) and those with LIC >15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC <7, LIC 7-≤15 and LIC >15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase (p <0.001), respectively. Similarly, at 36 months, the mT2* had increased by 71% (Mean abs. change, 10.3 ±6.6 ms) in the LIC <7 mg/g group; a 31% increase (5.3 ±5.0 ms) had occurred in the LIC 7– ≤15 mg/g group; and an 18% (3.3 ±6.0 ms) increase (p <0.001) had occurred in the LIC >15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher:Novartis Pharma: Honoraria, Research Funding. Aydinok:Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini:Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali:Novartis Pharma: Employment. Martin:Novartis Pharma: Employment. Pennell:Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria.

Prospective, Multinational/Regional, Non-Interventional Study to Assess Treatment Practices in Anemia Patients Prone to Iron Overload: Results from the 3-Year Transfusional Hemosiderosis Registry (TORS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2152-2152
Author(s):  
Noppadol Siritanaratkul ◽  
Jong Wook Lee ◽  
Jun Ma ◽  
Mustafa Pehlivan ◽  
Elena Volodicheva ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Final Visit ◽  
Common Disease ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Transfusion Therapy ◽  
Geographical Regions ◽  
Median Change

Abstract Background: Diseases whose treatment requires chronic transfusion therapy are relatively rare, and many have higher prevalence among certain ethnic groups and geographic regions. In these geographical regions, the patterns of care for these diseases and the epidemiology of iron overload (IOL) and other complications of treatment are currently undefined. To improve patient (pt) outcomes, it is important to understand how to diagnose, monitor, and manage these diseases. The TORS study aimed to collect information on a large number of newly diagnosed pts with various types of anemia and hemoglobinopathies to assess pt management considering diagnostic criteria and treatment pattern with iron chelation therapy (ICT) across various geographical regions. Methods: Inclusion and exclusion criteria were defined earlier by Siritanaratkul et al, EHA. 2015. Pts aged >2 years requiring chronic transfusion therapy with newly diagnosed anemias (<12 months from diagnosis), including low and intermediate-1 myelodysplastic syndromes (MDS), aplastic anemia (AA), and other transfusion-dependent (TD) anemias were enrolled. Pts were recruited from various geographical regions and were classified according to pt numbers, ethnicity and health care system as geo-1: Hong Kong, South Korea, Taiwan, Thailand; geo-2: China; geo-3: Tunisia, Morocco, Algeria, South Africa, Russia; geo- 4: Turkey. Pts were evaluated at baseline (BL) and at follow-up visits according to the standard practice for up to 3 years or until death. Results: Of the 564 pts (including 57 pts aged ≤18 years), 58.5% (n=330) were diagnosed with MDS, 31.2% (n=176) with AA, 10.1% (n=57) with other TD anemias. Diagnosis of 1 pt was missing. The mean age (±SD) was 51.9±23.87 years (range, 2-92); 49.5% of pts (n=279) were male. 97.2% (321/330) of MDS pts were classified using the WHO classification. In 89.0% of MDS pts, a risk assessment according to IPSS score was performed. Pts known to have received transfusions during the study include 92.6% (163/176) of AA, 68.4% (226/330) of MDS, and 93% (53/57) of other TD anemias. If analyzed by geographical region, 72.4% (126/174) of geo-1, 49.7% (99/119) of geo-2, 92% (115/125) of geo-3, and 70.5% (103/146) of geo-4 pts received transfusions during the study. At BL, serum ferritin (SF) was only available in 34.5% (195/564) of overall pts (50.9% [82/161] of chelated; 28% [113/403] of non-chelated pts) (Table 1). If analyzed by disease, among chelated pts, 38.4% (15/39) of AA, 57.1% (52/91) of MDS, and 48.3% (15/31) of other TD anemias had BL SF values. SF was available in 35% (20/57) of pediatric pts at BL (39.2% [11/28] of chelated; 31% [9/29] of non-chelated pts). In the overall pt population, data on ICT were available in 26% (13/50) of geo-1, 63.6% (7/11) of geo-2, 51.2% (20/39) of geo-3, and 68.8% (42/61) of geo-4 pts. At the final visit, the overall median change in SF from BL was -67.0 ng/mL. Among the pts receiving ICT (n=161), median change in SF from BL was -325.6 ng/mL (-433.5 in AA, +483.5 in MDS, and -1113.0 in TD anemias) at final visit. Among the pts without ICT (n=403), the median change in SF from BL was +116.7 ng/mL (+116.2 in AA, +163.2 in MDS and -306.5 in TD anemias). Among the pts with ICT (n=161), median change in SF from BL was +395 in geo-1, +113.5 in geo-3, and -433.5 in geo-4 at the final visit (pt data not available for geo-2). Among the pts without ICT (n=403), median change in SF from BL was +70.1 in geo-1, -170.6 in geo-2, -71.7 in geo-3, and +348.7 in geo-4 pts. Conclusions: In this large observational study, MDS was the most common disease type. This was potentially biased by site selection. Although the majority of pts received transfusion therapy leading to IOL, the awareness of IOL was low if measured by the availability of SF at BL and at each of the following visits. Consequently, many pts did not receive ICT. Interestingly, the majority of the MDS pts were classified according to WHO and stratified according to the recommended IPSS risk score, confirming that these guidelines are part of the standards of care in the clinical practice regardless of the geographic zone or the healthcare system. Overall, these results suggest that diagnosis and management practices of IOL and the underlying anemias may still be suboptimal in many parts of the world. Therefore, there is a need to improve local or regional understanding of IOL and its clinical consequences based on feasible therapeutic options in those regions. Disclosures Siritanaratkul: Janssen-Cilag: Research Funding; Novartis: Research Funding; Roche: Research Funding; Pfizer: Research Funding. Volodicheva:CELLTRION, Inc.: Research Funding. Wong:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Louw:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Han:Novartis: Employment. Losco:Novartis: Employment.

A Randomised 1 Year Study Evaluating the Impact of Vitamin C Supplementation on Systemic Iron Parameters of Iron Overload in Thalassemia Major Patients on Long-Term Treatment with Deferasirox

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1288-1288
Author(s):  
Yesim Aydinok ◽  
Metin Delebe ◽  
Gunes Basol ◽  
Selen Bayraktaroglu ◽  
Nihal Karadas ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Thalassemia Major ◽  
Average Dose ◽  
Advisory Committees ◽  
Baseline Characteristics ◽  
Labile Iron ◽  
The Impact

Abstract Background Ascorbic acid (AA) supplementation has traditionally been used in iron overloaded patients as means to increase iron chelation efficacy and replenish AA oxidized by labile iron found in those patients. The rationale leaned on AA's ability to render stored iron accessible to chelation, as found in urinary iron excretion following deferoxamine infusion. However, as AA increases labile iron redox-cycling and ensuing toxicity, we set to assess the long term benefits versus toxicity risks of the combined chelator-AA treatment. Objectives Perform a prospective, open-label, randomized and controlled 1 year study on thalassemia patients treated with deferasirox (DFX) in order to assess the effects of AA supplementation on: a. markers of systemic iron overload in selected organs and in plasma and b. markers of plasma labile iron (LPI) as potential contributors to oxidative stress toxicity. Patients and Methods Enrolment: 22 beta thalassemia major (TM) patients ≥10 years treated >2 years with DFX. Exclusion: cardiac dysfunction/arrhythmia or mT2* MRI <6 ms. Study: patients previously unexposed to AA received once-daily DFX (up to 40 mg/kg/d) with or without 125 mg AA for 1 year. All parameters were measured at baseline (BL); serum ferritin (SF) monthly, liver iron (LIC by MRI) and cardiac iron (mT2*MRI) after 1y. e-LPI (surrogate NTBI marker) and LPI (plasma redox-active labile iron marker) were assessed at BL, mo 1 & 6 by FeROS™ (Aferrix, Ltd) and fasting plasma AA at BL and EOS (fluorimetrically). Blood samples were withdrawn on the morning of transfusion day, 24 hours after last DFX (+/- AA) administration. Safety was followed using laboratory and clinical tests. AA levels were also determined in 23 healthy individuals (age and gender matched). Results 22 TM patients were enrolled (mean age 23.5, range 10-34 y). The average dose ± SD of DFX given to all 22 patients was 38±4.5 mg/kg/d. 11 patients were randomised to receive DFX and the others with DFX supplemented with 125 mg AA (mean 2.4±0.5, range 1.9-4.2 mg/kg) for 1 year. At BL, the AA levels were significantly lower in the TM group compared to controls (2.44 ± 3.38 vs 9.60± 4.36 mg/dl respectively, p<0.000001). 11 of 22 patients had AA levels >-2SD of control group whereas the other 11 patients showed normal ranges of AA. The AA deficient patients were those that showed significantly higher SF, LIC and lower mT2* at BL (Table 1). In the DFX+AA arm, 5/11 (45%) patients had subnormal AA levels at BL but attained normal status after 1 year, as did all others on AA. Of the 5/11 (45%) DFX-treated patients that did not receive AA had normal BL AA and only 2/11 maintained normal AA status at EOS. A significant correlation was obtained between BL SF, LIC and mT2* and e-LPI (r 0.49, p 0.025; r 0.57, p 0.01; r -0.43, p 0.057 respectively) but not with LPI. The changes associated with DFX alone or with AA from BL to EOS were subtle for all parameters measured (Table 2). Importantly, eLPI and LPI remained at basal levels throughout 6 months treatment in both arms. With DFX alone, LPI were 0.34±0.30 units (mM iron) (BL) & 0.63±0.58 (6 mo); eLPI: 1.71±1.93 at BL & 2.48±3.11 (6 mo). DFX+AA: LPI were 0.33±0.46 (BL) & 0.35±0.44 (6 mo); eLPI: 2.13±1.71 (BL) & 1.78±1.51 (6 mo). Conclusions TM patients on long term DFX without AA supplementation showed subnormal, AA levels. This was most pronounced in TM patients with higher liver and heart iron. The addition of AA to DFX normalized the AA levels but did not increase the e-LPI and LPI during 6 mo, indicating no apparent risk of iatrogenic toxicity by AA to DFX. Moreover, AA may enhance the efficacy of DFX in cardiac and hepatic iron. The small rise in SF versus fall in LIC in the DFX+AA arm might need further exploration. Table 1 Baseline characteristics of patients based on AA status Table 1. Baseline characteristics of patients based on AA status Table 2 Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Table 2. Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Disclosures Aydinok: Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cerus: Research Funding; Shire: Research Funding. Cabantchik:Aferrix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hinoman: Consultancy; Novartis Pharmeceuticals: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau.

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