Transfused Myelodysplastic Syndromes (MDS) Patients Have Severe Iron Overload and Relevant Improvements in Iron Burden and Liver Function with Deferasirox Treatment: Results From a Pooled Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5019-5019
Author(s):  
Norbert Gattermann ◽  
Peter L. Greenberg ◽  
Akio Urabe ◽  
Dany Habr ◽  
Euloge E. Kpamegan ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Liver Function ◽  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Pooled Analysis ◽  
Advisory Committees ◽  
Absolute Change ◽  
Starting Dose

Abstract Abstract 5019 Background: MDS patients receiving chronic transfusions can develop significant iron accumulation in key organs such as the liver following 10–20 transfusions (Porter et al. BJH 2001). The diagnosis and monitoring of iron overload, as well as the effect of iron chelation therapy in MDS patients, is often based on serum ferritin (SF), with limited data on liver iron concentration (LIC), primarily due to the biopsy-related increased risk of bleeding and infections in these patients. However, LIC is clinically a more robust and direct measure of body iron burden and with the availability of non-invasive determination of LIC by MRI, LIC assessment has become more practical in MDS patients. This pooled analysis focuses on LIC assessments from a population of 71 MDS patients who completed 1 year of treatment with deferasirox (Exjade®), including assessment of the relationship between LIC vs SF and alanine aminotransferase (ALT). Methods: Analysis is based on 1-year pooled data from iron-overloaded patients with MDS who were enrolled in 4 open-label single-arm deferasirox studies: US02 (Low/Int-1 MDS patients, starting dose 20 mg/kg/day); 2409 (MDS patients with life expectancy >1 yr, starting dose 10–30 mg/kg/day); 108 (MDS patients with life expectancy >1 yr, dosing 5–40 mg/kg/day), and 2204 (Low/Int-1 MDS patients, starting dose 10–30 mg/kg/day). LIC was assessed in the US02, 2409 and 2204 studies using R2 MRI (St Pierre et al. Blood 2004). In the 108 study, LIC was assessed by magnetic liver susceptometry using a superconducting quantum interference device (SQUID) or ultrasound-guided percutaneous liver biopsy; LIC values obtained by SQUID were multiplied by a factor of 2 to correct for the underestimation of LIC by SQUID compared to biopsy (Porter et al. EJH 2008). Datasets were pooled for baseline (BL) characteristics, as well as LIC, SF and ALT at BL and end of study (EOS). Correlations were evaluated on a Pearson's correlation coefficient. Results: 71 patients (56.3% male) were assessed with a mean age of 65 years (range 16.5–82.0). Mean transfusional iron intake ± SD was 0.31 ± 0.12 mg/kg/day. Mean actual deferasirox dose was 19.6 ± 6.5 mg/kg/day. At BL, mean ± SD LIC was 20.5 ± 14.6 mg Fe/g dw (BL LIC <7 mg Fe/g dw, 21.1%; ≥7 mg–≤15 mg Fe/g dw, 23.9%; and >15 mg Fe/g dw, 54.9%). Median BL SF was 2620 ng/mL (range 538–12,639) (BL SF ≤2500 ng/mL, 47.9%; >2500–≤5000 ng/mL, 32.4%; and >5000 ng/mL, 15.5%). With 1 year of DFX, mean ± SD LIC decreased to 13.9 ± 13.1 mg Fe/g dw (mean absolute change –6.6 mg Fe/g dw). In patients with BL LIC <7 mg Fe/g dw (n=15), LIC was maintained with a mean absolute change of 1.0 ± 2.8 mg Fe/g dw, whereas in patients with BL LIC ≥7 mg Fe/g dw (n=56), LIC was reduced by –8.6 ± 10.7 mg Fe/g dw from BL. The proportion of MDS patients with LIC ≥7 mg Fe/g dw reduced from 78.9% at BL to 59.2% at EOS, with 50.7% of patients achieving a decrease in LIC of ≥30%. Median SF decreased to 2035 ng/mL (range 158–10520 ng/mL) with median absolute change from baseline of –630 ng/mL. There was a significant correlation between BL LIC and SF (R=0.548; P<0.0001). Change in LIC significantly correlated with change in serum ferritin (R=0.336; P=0.0042, Figure A). Mean ALT decreased from 55.9 to 38.9 U/L (absolute change –17.0). The change in LIC correlated with the change in ALT (R=0.397, P=0.0006, Figure B). Conclusions: This pooled analysis in a large cohort of transfusion-dependent MDS patients with LIC assessment shows significantly elevated LIC, with a high proportion of patients (55%) having severely elevated LIC of >15 mg Fe/g dw, a level known to markedly increase liver dysfunction and other iron overload-related complications. One year of treatment with deferasirox produced relevant reductions in LIC, an outcome possibly indicative of a clinical benefit. SF and ALT (an important indicator of liver function) also decreased, with reductions correlating with those of LIC. These findings indicate that correction of moderate-to-severe iron overload in MDS patients is associated with a parallel improvement in liver function. Disclosures: Gattermann: Novartis Pharma: Honoraria, Research Funding. Greenberg:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Habr:Novartis Pharma: Employment. Kpamegan:Novartis Pharma: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Optimizing Iron Chelation Therapy with Deferasirox for Non-Transfusion-Dependent Thalassemia Patients: 1-Year Results from the Phase IV, Open-Label Thetis Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2153-2153
Author(s):  
Ali T Taher ◽  
M Domenica Cappellini ◽  
Yesim Aydinok ◽  
John B. Porter ◽  
Zeynep Karakas ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Iron Chelation ◽  
Relative Reduction ◽  
Average Dose ◽  
Advisory Committees ◽  
Absolute Change

Abstract Background: Efficacy and safety of iron chelation with deferasirox (Exjade®; DFX) 5 and 10 mg/kg/day (escalated to max: 20 mg/kg/day) in non-transfusion-dependent thalassemia patients, was established in the placebo-controlled, THALASSA study; Taher et al Blood 2012;120:970-977. THETIS added to this evidence by investigating a broader patient population, including non-transfusion-dependent congenital anemia patients and those treated with concomitant medications (eg hydroxyurea) and by evaluating early escalation with higher DFX doses according to liver iron concentration (LIC; max: 30 mg/kg/day). Methods: Patients ≥10 yrs of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw]) and serum ferritin (SF) ≥300 ng/mL were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed); Hb S/β thalassemia; active hepatitis B/C; cirrhosis; history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase (ALT) >5×the upper limit of normal (ULN), serum creatinine >ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio >1.0 mg/mg. All patients started DFX at 10 mg/kg/day. At week 4, DFX was increased according to baseline (BL) LIC: LIC >15, 20 mg/kg/day; LIC >7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day. At week 24, DFX was adjusted further: LIC >15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC >7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC <3 or SF <300 ng/mL, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 ng/mL (max 10 mg/kg/day). The primary efficacy endpoint was absolute change in LIC from BL to week 52. Secondary endpoints included absolute change in LIC from BL to week 24 and change in SF from BL to week 52. Results: 134 patients were enrolled consisting of β thalassemia intermedia (n=69), Hb H disease (n=40), Hb E/β thalassemia (n=24) and congenital dyserythropoietic anemia (n=1) patients. Mean actual daily DFX dose ± SD over 1 yr (considering dose adjustments) was 14.70 ± 5.48 mg/kg/day. Mean LIC ± SD decreased significantly from 15.13 ± 10.72 mg Fe/g dw at BL to 8.46 ± 6.25 mg Fe/g dw at week 52 (absolute change, ‒6.68 ± 7.02 mg Fe/g dw [95% CI: -7.91, -5.45]; P <0.0001). At the last assessment, an absolute decrease in LIC of ≥3 mg Fe/g dw was observed in 86 (64.2%) patients and a ≥30% relative reduction in LIC in 81 (60.4%) patients. Reduction in LIC was greater in patients with higher BL LIC, with these patients receiving a higher than average dose (Figure). Median SF (range) decreased from 1001 (232-6638) ng/mL at BL to 669 (200-4315) ng/mL at week 52 (absolute median change, -304 [-5307 to -1669] ng/mL). 112 (83.58%) patients completed 1 yr. Patients discontinued primarily because of withdrawal of consent (n=10, personal/logistical reasons). Adverse events (AE) regardless of causality were reported in 97 (72.4%) patients and were unaffected by average dose. AEs with a suspected relationship to DFX were reported in 42 (31.3%) patients; most commonly, gastrointestinal (abdominal discomfort, diarrhea, nausea; n=6 each). One patient had a suspected drug-related serious AE (pancreatitis) that lasted 11 days; DFX was withheld for the duration, then restarted. One patient discontinued because of an AE (extramedullary hematopoiesis) and one death occurred (pneumonia leading to cardiac failure); neither suspected as drug-related. One patient had an elevated BL ALT 2×ULN that increased to >5×ULN on one occasion; BL bilirubin levels were 2×ULN and alkaline phosphatase 1.5×ULN; without dose adjustment or interruption, all parameters improved better than baseline values by week 52. No patient had two consecutive serum creatinine increases >33% above BL or >ULN. All patients with notable renal or liver laboratory values continued treatment. Conclusions: DFX 10 mg/kg/day (escalated to max: 30 mg/kg/day) resulted in significant and clinically relevant reductions in iron overload, with a similar safety profile as reported in THALASSA (in both DFX- and placebo-treated patients). With early dose escalation at week 4 with further adjustment at week 24, patients with a higher iron burden received higher DFX doses. These results support early dose escalation of DFX to optimize chelation in more heavily iron-overloaded patients with non-transfusion-dependent anemias. Disclosures Taher: Novartis: Honoraria, Research Funding. Cappellini:Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Karakas:Novartis: Research Funding. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GPO, Thailand: Honoraria, Research Funding; Shire: Research Funding. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. Wang:Novartis: Employment. Zhu:Novartis: Employment. Joaquin:Novartis: Employment. Uwamahoro:Novartis: Employment.

Safety of Deferasirox (Exjade®) in Myelodysplastic Syndromes (MDS) and Non-MDS Patients with Transfusional Iron Overload: A Pooled Analysis Focusing On Renal Function.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1768-1768 ◽  
Author(s):  
Mathias Schmid ◽  
M. Domenica Cappellini ◽  
John B. Porter ◽  
Peter L. Greenberg ◽  
Tomasz Lawniczek ◽  
...  
Keyword(s):  
Renal Function ◽  
Abdominal Pain ◽  
Renal Dysfunction ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Pooled Analysis ◽  
Advanced Age ◽  
Advisory Committees ◽  
Starting Dose

Abstract Abstract 1768 Poster Board I-794 Background Assessment of the safety profile, in particular renal function, of the oral iron chelator deferasirox (Exjade®) is of particular relevance in MDS patients (pts), given their advanced age and associated decline in renal function. This 1-yr pooled analysis characterizes the safety profile of deferasirox in a large population of MDS and non-MDS pts (β-thalassemia [β-thal] and other anemias [sickle cell, Diamond-Blackfan, aplastic and other]), with emphasis on renal function. Methods Analysis is based on 1-yr pooled data from iron-overloaded pts who were enrolled in five open-label deferasirox studies: US02 and US03 (single-arm (SA), Low/Int 1 MDS pts, starting dose 20 mg/kg/day); 2409 (SA, pts with transfusional hemosiderosis, starting dose 20 mg/kg/day); 107 (randomized trial in β-thal pts, dosing 5–40 mg/kg/day) and 108 (SA, pts with chronic anemias, dosing 5–40 mg/kg/day). Datasets pooled: baseline (BL) characteristics, dosing, transfusion, adverse events (AEs) and laboratory data. Results 1798 pts were assessed (951 β-thal; 584 MDS, 263 other). MDS pts were older (median age 71 yrs) compared with those with β-thal (25 yrs) and other anemias (38 yrs). Mean actual dose of deferasirox (mg/kg/day): β-thal pts 23.5; MDS pts 20.3; other 19.9. Mean transfusional iron intake (mg/kg/day): 0.34, 0.32 and 0.23 in β-thal, MDS and other anemias, respectively. At 1 yr, 88%, 53% and 69% of β-thal, MDS and other pts remained in the study, respectively. Most frequent reasons for discontinuation: AEs (n=42 [4%] β-thal; n=115 [20%] MDS; n=34 [13%] other anemias). Frequency of drug-related AEs was similar for MDS (68%) and other anemias (63%) compared with 49% for β-thal. Most common drug-related AEs in β-thal, MDS and others, respectively, were: diarrhea (11%; 37%; 23%), nausea (7%; 15%; 20%), vomiting (3%; 8%; 8%); rash (11%; 8%; 6%); abdominal pain (6%; 7%; 8%) and upper abdominal pain (4%; 5%; 8%). 64 deaths occurred (none assessed as related to deferasirox by the investigator); 4 (primarily cardiac), 47 (primarily infections, hemorrhages, progression to AML, cardiac events) and 13 (primarily infections) in the β-thal, MDS and other pts, respectively. BL versus last available creatinine clearance (CrCl) were analyzed graphically for MDS pts with/without investigator-reported renal dysfunction AEs (Figure). CrCl for the majority of β-thal and non-MDS pts was >60 mL/min at BL (not shown), while in the MDS group, as expected, there were more pts with CrCl <60 mL/min and reported renal dysfunction AEs (Fig. A). To evaluate pts with BL CrCl <60 mL/min, an expanded view was created (Fig. B). A greater proportion of MDS pts with renal AEs was reported in the 20–<30 mL/min (43%) and 30–<40 mL/min category (30%), versus the 40–<50 mL/min (13%) and 50–<60 mL/min categories (7%). Exploratory logistic regression modeling confirmed odds of reporting a renal dysfunction AE were 4 and 22 times for pts with CrCl 40–<60 mL/min and <40 mL/min, respectively, compared to pts with CrCl ≥60 mL/min. Pts with BL CrCl <40 mL/min (n=6) were >70 yrs with primarily pre-existing chronic renal insufficiency, diabetes, hypertension and congestive heart failure. Pts with BL CrCl 40–60 mL/min had fewer pre-existing conditions, but still had reported renal dysfunction AEs. In about half of cases with BL CrCl <60 mL/min, reported renal dysfunction AEs were not associated with a clinically significant increase in SCr and corresponding CrCl decline, consistent with investigators' discretion in reporting. Conclusions This comprehensive assessment of MDS and non-MDS pts with transfusional iron overload confirmed the known safety profile of deferasirox; with the most frequent drug-related AEs reported as gastrointestinal events. The findings were also consistent with the clinical features of MDS such as advanced age and co-morbidities. Pts with BL CrCl <40 mL/min were more likely to report renal dysfunction AEs and less likely to be able to compensate for additional stresses on their existing decreased renal function, given their pre-existing co-morbidities and advanced age. Deferasirox may be used in pts with BL CrCl 40–<60 mL/min with close monitoring, and should not be used in pts with BL CrCl <40 mL/min. Disclosures 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. 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. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lawniczek:Novartis Pharma AG: Employment. Glaser:Novartis Pharma AG: Employment. Dong:Novartis Pharmaceuticals: Employment. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials.

Clinical Parameters in 391 Iron-Overloaded Patients with Lower-Risk MDS Enrolled in a Prospective, Non-Interventional Multicenter Registry.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4834-4834
Author(s):  
Guillermo Garcia-Manero ◽  
Billie J. Marek ◽  
Roger M. Lyons ◽  
Noelia Martinez-Lopez ◽  
Carole Paley ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Lower Risk ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Advisory Committees ◽  
The Impact

Abstract Abstract 4834 Introduction Despite recent improvements in therapies for patients with myelodysplastic syndromes (MDS), 60–80% will require continuing packed red cell blood (pRBC) transfusions for prolonged periods. Complications resulting from the iron burden may, therefore, become clinically significant for many patients during the course of their disease. Patients with lower-risk MDS have a greater chance of developing the long-term toxicity of iron overload because of their prolonged survival, and are more likely to benefit from effective iron chelation therapy. This report describes data from a registry designed to study the impact of iron overload and iron chelation therapy on organ function and survival in patients with lower-risk MDS. Methods This is an ongoing, prospective, non-interventional, multicenter 5-year registry in 107 US centers, enrolling 600 patients (aged ≥18 years) with lower-risk MDS (by WHO, FAB and/or IPSS criteria) and transfusional iron overload (defined as serum ferritin ≥1000 μg/L and/or having received ≤20 cumulative pRBC units and/or an ongoing transfusion requirement ≥6 units every 12 weeks). Follow-up will be performed at least every 6 months for a maximum of 60 months or until death. Recommended assessments include serum ferritin, creatinine, calculated creatinine clearance, echocardiograms, and endocrine and hematological status. Results As of May 31 2009, 391 patients have enrolled in the registry. Demographic data are available from 389 patients. Median age: 74.4 years (range 21–99); male: 218, female: 171; ethnicity: 331 Caucasian (85%), 25 African-American (6%), 24 Hispanic (6%), five Asian (1%), two Native American (0.5%), and two other (0.5%). The median time since diagnosis (n=385) was <3 years in 217 patients (56%); ≥3–<5 years in 72 (19%); ≥5–<7 years in 48 (12%); and ≥7 years in 48 (12%). The MDS classification of the patients by WHO, FAB and IPSS, as well as patients' serum ferritin and transfusion burden, are summarized in the table. The most frequent concomitant conditions classified by organ (n=384 patients) were: 205 (53%) patients with vascular, 160 (42%) endocrine, and 171 (45%) cardiac dysfunction. At registry entry, 249 patients were receiving erythropoietin; 61 granulocyte colony stimulating factor; seven hydroxyurea; 25 thalidomide (Thalomid); 147 5-azacytidine (Vidaza); 95 lenalidomide (Revlimid) and 90 decitabine (Dacogen). 137 of 391 (35%) patients were on iron chelation therapy at study entry: 34 (9%) received deferoxamine for mean and median treatment durations of 803 and 383 (range 1–4386) days, respectively, while 117 (30%) received deferasirox for mean and median durations of 488 and 396 (9–1269) days, respectively. Calculated creatinine clearance was normal (>80 mL/min) in 37 (9%) patients; mildly abnormal (51–80 mL/min) in 30 (8%); and moderately abnormal (30–50 mL/min) in nine (2%) patients. Conclusions These baseline data indicate the demographic distribution as well as the co-morbidities associated with lower-risk MDS patients. In spite of recent guidelines, fewer than 50% of iron-overloaded patients are receiving any iron chelation treatment, despite the presence of cardiac, vascular and endocrine concomitant conditions in 40-54% of patients. Recent retrospective data highlights the impact of chelation on mortality in lower-risk MDS patients. This ongoing registry will prospectively assess the impact of iron chelation on survival and organ function in iron-overloaded patients with lower-risk MDS. Disclosures Lyons: Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Research Funding. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Efficacy and Safety of Deferasirox in Chinese Patients with Non-Transfusion-Dependent Thalassemia: 1-Year Results from the Thetis Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4570-4570
Author(s):  
Yong-Rong Lai ◽  
Rong Rong Liu ◽  
M Domenica Cappellini ◽  
Yesim Aydinok ◽  
John B Porter ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Chinese Patients ◽  
Relative Reduction ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Absolute Change

Abstract Background: Although non-transfusion-dependent thalassemias (NTDT) and non-transfusion-dependent congenital or chronic anemias are found in Southern China, they are relatively rare diseases in China and there are little data evaluating iron chelation in Chinese patients. This 1-year analysis from the THETIS study investigated the efficacy and safety of deferasirox in a large subpopulation of Chinese patients. Early escalation of deferasirox doses (max: 30 mg/kg/day) was evaluated according to liver iron concentration (LIC). Methods: THETIS is an open-label, single-arm, multicenter, Phase IV, 5-year study with the primary endpoint after 1 year of treatment. For this subanalysis, Chinese patients ≥10 years of age with iron overload (LIC ≥5 mg Fe/g dry weight [dw] and serum ferritin [SF] ≥300 ng/mL) were enrolled. Exclusion criteria included: blood transfusions within 6 months of study enrollment or anticipated regular transfusions (unplanned transfusions allowed), Hb S/β thalassemia, active hepatitis B/C, cirrhosis, history of clinically relevant ocular and/or auditory toxicity; on two consecutive measurements: alanine aminotransferase >5× the upper limit of normal (ULN), serum creatinine >ULN, creatinine clearance ≤40 mL/min, or urine protein/urine creatinine ratio >1.0 mg/mg. All patients started deferasirox at 10 mg/kg/day. At week 4, deferasirox was increased according to baseline LIC (LIC >15, 20 mg/kg/day; LIC >7-≤15, 15 mg/kg/day; LIC ≥5-≤7, 10 mg/kg/day). At week 24, deferasirox was adjusted further: LIC >15, +5-10 mg/kg/day (max 30 mg/kg/day); LIC >7-≤15, +5 mg/kg/day (max 20 mg/kg/day); LIC ≥3-≤7, same dose. If LIC <3 or SF <300, therapy was held and restarted at the previously effective dose when LIC ≥5 and SF ≥300 (max 10 mg/kg/day). This sub-analysis evaluated absolute change in LIC and SF from baseline to week 52. Results: 68 Chinese patients were enrolled (median age 26.0, range 10-63 years) with Hb H disease (n=35), β thalassemia intermedia (n=21) or Hb E/β thalassemia (n=12). Most patients received prior transfusions (n=56/68, 82.4%); 20/68 (29.4%) patients received prior chelation. 57/68 (83.82%) patients completed 1 year. Patients who discontinued were most commonly lost to follow-up (n=4) or withdrew consent (n=3, personal or logistical reasons). Mean actual daily deferasirox dose ± standard deviation (SD) over 1 year (considering dose adjustments), was 16.21 ± 5.61 mg/kg/day. Mean LIC ± SD at baseline was 17.75 ± 12.37 mg Fe/g dw in Chinese patients, which decreased to 9.35 ± 6.83 mg Fe/g dw at week 52 (absolute change from baseline, -8.51 ± 8.58 mg Fe/g dw [95% CI -10.69 to -6.33]). Patients with higher LIC at baseline experienced a greater reduction in LIC by week 52 (Figure). Furthermore, 48 (70.6%) Chinese patients achieved an absolute decrease in LIC of ≥3 mg Fe/g dw, and 46 (67.6%) patients achieved a ≥30% relative reduction in LIC at the last assessment. At week 52, LIC was <3 mg Fe/g dw in 5 (7.4%) patients. Median SF (range) decreased in Chinese patients from a baseline of 1580 (333-6638) ng/mL to 872 (267-4315) ng/mL at week 52 (absolute median change, -423 [-5307 to -1669] ng/mL). At week 52, SF was <300 ng/mL in 1 (1.5%) patient. Adverse events (AE) regardless of causality were reported in 40 (58.8%) Chinese patients. Drug-related AEs were reported in 18 (26.5%) Chinese patients, most commonly gastrointestinal (abdominal discomfort, n=2; diarrhea and hematochezia, n=1 each) or skin related (rash, n=3; eczema, n=1). No patients discontinued because of AEs. One death occurred during the study (pneumonia leading to cardiac failure) that was not suspected to be drug-related. No patient had two consecutive serum creatinine increases of >33% above baseline or >ULN. No patient discontinued treatment due to notable liver or renal laboratory values. Conclusions: Deferasirox at 10 mg/kg/day escalated to a maximum of 30 mg/kg/day effectively reduced iron burden in Chinese patients. AEs were consistent with the known safety profile for deferasirox. Early dose escalation at week 4 and further adjustment at week 24 ensured that patients with iron overload achieved clinically relevant reductions in iron burden. These results were in alignment with the THETIS primary efficacy analysis, supporting early dose escalation of deferasirox to optimize chelation in more heavily iron-overloaded Chinese NTDT patients. Figure 1. Figure 1. Disclosures Cappellini: Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Zhu:Novartis: Employment. Wang:Novartis: Employment. Qi:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding.

Detection and Treatment of Iron Overload in Red Blood Cell (RBC) Transfusion-Dependent Myelodysplastic Syndromes (MDS): A European Survey.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4830-4830 ◽  
Author(s):  
Aristoteles Giagounidis ◽  
Kathy Heptinstall ◽  
Didì Jasmin ◽  
Susanna Leto di Priolo ◽  
Susanne Ille ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Advisory Committees ◽  
Patient Age ◽  
European School ◽  
Poor Patient ◽  
Patient Prognosis ◽  
Rbc Transfusion

Abstract Abstract 4830 Background Repeated RBC transfusions in patients with MDS cause progressive iron accumulation in the liver, heart and endocrine glands, with potentially deleterious effects on those organs. Iron chelation therapy (ICT) has been shown to ameliorate the toxicity of iron overload in patients with thalassemia. Although the clinical consequences of iron overload and effects of ICT have not been as well demonstrated in patients with MDS, country-specific guidelines for monitoring and treating iron overload have been published. To gain a better understanding of the detection and management of iron overload in Europe, the MDS Iron-overload Detection Insight Survey (MIDIS) was conducted in European physicians treating transfusion-dependent patients with MDS. The MIDIS was conducted by the MDS Foundation and the European School of Haematology in partnership with Novartis Oncology. Methods European physicians who were seeing at least one transfusion-dependent patient with MDS in an average 6-month period were invited to take part in the survey. The 15-minute questionnaire was web- or paper-based and comprised a number of closed- and open-ended questions. Results 338 physicians from 27 European countries participated in the survey. Respondents had a mean age of 44 years (54% M, 46% F), a mean of 18 years' experience, and were fully qualified (87%) or in training (13%). 59% worked at teaching hospitals, 28% in general hospitals and 13% in other institutions. Respondents saw a mean of 19 RBC transfusion-dependent patients with MDS per 6 months. 46% and 27% of respondents noted that detection of iron overload in transfusion-dependent MDS was ‘very important’ or ‘important’, respectively. 53% replied that they monitored serum ferritin levels in those patients quarterly, while 26% said that how often they monitored depended on the frequency of transfusions. Respondents said that serum ferritin always (46%) or sometimes (47%) had an impact on treatment decisions. The main barriers to detecting iron overload were: poor patient prognosis (relevant barrier in 30% of respondents); low frequency of serum ferritin monitoring (30%); and lack of awareness about guidelines (27%) and about the risks of iron overload (23%). Other barriers were: a low priority for iron-overload screening (23%); and perceptions about the importance of iron overload in MDS (17%). Factors that positively influenced detection of iron overload included: >20 RBC units received (relevant trigger in 76% of respondents); introduction of serum ferritin as a standard test (76%); and awareness of the potential risks of frequent transfusions (75%). 37% and 31% of respondents believed that treating iron overload in RBC transfusion-dependent patients with MDS was ‘very important’ or ‘important’, respectively. 90% of physicians prescribed ICT in those patients; however, a mean of only 38% of patients received ICT. Factors leading respondents to initiate ICT included: patient age of 55–64 years (important in 77% of respondents); serum ferritin levels of >1000 ng/mL (76%); candidacy for allogeneic SCT (76%); need to prevent organ dysfunction (74%); ≥2 RBC units transfused per month (71%); lifetime transfusions of >20 RBC units (68%); and convenience of oral ICT (67%). The barriers to initiating ICT mostly related to poor patient prognosis (72%) and patient age ≥85 years (50%), while others included: comorbidities limiting prognosis (34%), including renal problems (27%); Int-2 or High IPSS-risk MDS (31%); and expected non-compliance (28%). There were differing opinions regarding the importance of some of the barriers to initiating ICT; 31% of respondents said that a high-risk classification and 28% said expected non-compliance were high barriers, while 25% and 23%, respectively, thought that these were weak barriers. Conclusions Most respondents were experienced European physicians with a keen interest in MDS. 73% and 68% of physicians said they believe that detecting and treating iron overload, respectively, were ‘important’ or ‘very important’ in transfusion-dependent patients with MDS. In total, 90% of them prescribed ICT to their transfused patients with MDS. This survey showed that older age and poor patient prognosis (especially based on IPSS classification) were the greatest barriers to initiating ICT; however, the patient's physiological condition was also an important barrier. Disclosures Giagounidis: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Heptinstall:The MDS Foundation: The MDS Foundation is a 501(c)3 patient advocacy organization. We receive grants from companies, individuals and groups but have no contractual obligation to any of these donors, and our research or advocacy decisions are independent. Jasmin:European School of Haematology: Employment; The European School of Haematology receives unrestricted educational grants from Novartis Pharmaceuticals: Research Funding. Leto di Priolo:Novartis Farma S.p.A.: Employment, Equity Ownership. Ille:GfK SE, a market research agency that has been commissioned and paid by Novartis Oncology to conduct the MIDIS survey data collection: Employment. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Serum Ferritin, Labile Plasma Iron and Transferrin Saturation: Comparison Between Underlying Anemias with Transfusional Iron Overload Before and After Treatment with Deferasirox.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2126-2126 ◽  
Author(s):  
John B Porter ◽  
Mohsen Elalfy ◽  
Vip Viprakasit ◽  
Stephane Giraudier ◽  
Lee Lee Chan ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Full Range ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Serum Markers ◽  
Advisory Committees ◽  
The Relationship

Abstract Abstract 2126 Background: In patients with transfusion-dependent anemias, monitoring the efficacy of iron chelation therapy (ICT) using serum ferritin (SF) alone can sometimes be challenging; therefore, additional serum markers would be helpful. Furthermore, any differences between different anemias for the relationship between SF and other serum markers both before and in response to ICT may be useful to predict relative risk of iron-mediated toxicity between these conditions. Data from the 1-yr EPIC (Evaluation of Patients' Iron Chelation with Exjade®) trial allows assessment of iron parameters in a large cohort of patients with thalassemia, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Here we evaluate trends in liver iron concentration (LIC), transferrin saturation (TfSat) and labile plasma iron (LPI) in their relation to SF levels and assess systematic differences between underlying anemias. Relationships were assessed at baseline (BL), reflecting iron accumulation at study entry, and also at end of study (EOS), with changes reflecting iron excretion after 1 yr treatment with deferasirox. Methods: LIC, TfSat and LPI were measured at BL and at EOS for each underlying disease. Changes in these parameters as well as relationships between these parameters and SF were assessed by SF categories at BL and at EOS. For EOS measurements, last observation carried forward was used for all parameters (last post-BL available value), except for LPI, for which 1-yr visit was used. Pre-deferasirox dose LPI levels are reported. Results: Data from 1114 thalassemia patients, 336 MDS patients and 80 SCD patients were available for analysis. For all underlying anemias, LIC was higher at higher SF categories; in thalassemia patients for eg, with BL SF categories <1000, 1000–2000, 2000–3000, 3000–4000, 4000–5000, >5000 ng/mL, the mean LIC values at BL were 4.9, 9.0, 15.3, 22.1, 27.2, 32.5 mg Fe/g dw, respectively. Overall, mean TfSat was 89.6% (n=755) in thalassemia patients at BL and 96.1% (n=955) at EOS, compared with 82.5% (n=116) and 83.8% (n=171) in MDS patients, respectively. In SCD patients, TfSat was 61.3% (n=71) at BL and 64.1% (n=74) at EOS. TfSat was lowest in SCD patients across the full range of SF categories examined (Figure). At BL, TfSat was higher at higher SF categories in all diseases, with a similar trend at EOS, although at EOS this trend was more evident in MDS and SCD (Figure). Overall, mean LPI levels at BL and EOS were 1.25 μmol/L (n=472) and 0.59 μmol/L (n=818) in thalassemia patients, 0.53 μmol/L (n=221) and 0.14 μmol/L (n=147) in MDS patients, and 0.11 μmol/L (n=55) and 0.10 μmol/L (n=46) in SCD patients, respectively. LPI levels were highest in patients with thalassemia and lowest in SCD patients across SF categories (Figure). After 1 yr treatment with deferasirox, LPI levels were reduced in thalassemia and MDS patients, but there was no difference in patients with SCD. LPI was higher at higher SF categories in MDS patients at both BL and EOS, with a similar trend in SCD patients at EOS, although there was little relationship in thalassemia patients (Figure). Discussion: At matched SF levels and across a wide range of SF values, TfSat was lower in SCD patients, in comparison to thalassemia and MDS patients, both at BL and EOS. Similar observations have been reported previously and may contribute to the lower propensity for extra-hepatic iron accumulation in SCD patients. The mechanisms for this difference remain unclear, but could be attributed to sequestering of iron due to chronic inflammation in SCD. TfSat did not appear to decrease after 1 yr treatment with deferasirox, in any underlying anemia. The relationship of LPI to SF categories differed between underlying anemias; both at BL and EOS. At BL, SCD patients had low LPI values across the full range of measured SF values, whereas higher LPI levels at higher SF categories were most evident in MDS patients. Overall, LPI was highest in thalassemia patients. After 1 yr treatment with deferasirox, LPI was decreased in thalassemia and to a lesser extent in MDS patients, but there was no change from the low level at BL in SCD patients. The decrease in LPI in MDS and thalassemia at EOS may reflect the effects of residual plasma chelator 1 day after the previous dose and/or the decrease in storage iron over 1 yr of treatment. With further evaluation, LPI could become a useful marker of iron overload and chelation response in patients with MDS and possibly thalassemia. Disclosures: Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Viprakasit:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

scholarly journals Genome Wide Association Analysis of Iron Overload in the Trans-Omics for Precision Medicine (TOPMed) Sickle Cell Disease Cohorts

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 52-52
Author(s):  
Fayuan Wen ◽  
Angela Rock ◽  
Juan Salomon-Andonie ◽  
Gulriz Kurban ◽  
Xiaomei Niu ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Research Funding ◽  
Outcome Prediction ◽  
Advisory Committees ◽  
Significance Level ◽  
Association Analyses ◽  
Genome Wide ◽  
Genome Wide Significance

Introduction: Transfusional iron (Fe) overload is a significant problem among patients with chronic, transfusion-dependent anemias. Iron overload is an important problem in pediatric sickle cell disease (SCD) patients on chronic transfusion regimens predominantly for primary and secondary prevention of stroke. Coexistent hereditary iron overload conditions contribute to the iron overload phenotype in SCD. For example, the Q248H mutation (rs11568350) in SLC40A1, which encodes ferroportin (FPN), is associated with a mild tendency to increase serum ferritin in the general population and with increased ferritin levels in SCD patients. Nevertheless, the molecular mechanisms underlying the progression to iron overload in SCD patients are poorly understood and more sensitive markers for outcome prediction that can be applied at early clinical stages are lacking. We hypothesize that genetic variation modifies the risk for iron overload in SCD patients and seek to validate previously identified mutation and identify novel genetic markers of iron overload among participants from TOPMed SCD cohorts by performing whole genome sequencing (WGS) association analyses. Methods: The WGS was performed by several national sequencing centers sponsored by NHLBI's TOPMed program at an average depth of 30× using DNA from SCD patient blood samples. Variant calling was performed jointly across TOPMed studies for all samples using the GotCloud pipeline by the TOPMed Informatics Research Center. The TOPMed data Coordinating Center performed quality control for sample identity. The data across the following studies were shared through the database of Genotype and Phenotype (dbGaP) exchange area: Howard PUSH SCD (N=370), OMG SCD (N=636), Walk PHaSST SCD (N=381) and REDS-III Brazil SCD (N=2620) with a total sample size of 4007. The study was approved by the appropriate institutional review boards (IRB) and informed consent was obtained from all participants. Genome Wide Association Analysis of iron overload was carried out using the University of Michigan ENCORE server. We performed single variant tests to test the association of log-transformed serum ferritin levels with single nucleotide variants (SNVs) while adjusting for sex, age, self-reported race, numbers of lifetime red blood transfusions and genetic substructure (PC's 1-10). We used a significance threshold of p&lt;5×10-8 to report anassociation as genome-wide significant for common and rare genetic variants. Results: We first included PUSH SCD, OMG SCD and Walk PHaSST SCD cohorts with 840 serum ferritin samples in the WGS association analyses, which revealed at the genome-wide level a new rare variant rs137929759 (chr7:49538810 (GRCh38.p12), MAF=0.0043532, p=2.25×10−8). A few variants such as rs80097634 in gene AL163195.3 and RNASE11 (Chr14:20579417. MAF=0.050373, p=3.1×10-7) were close to the genome-wide significance level. We confirmed previously identified associations in SLC40A1 for ferritin (rs11568350, Chr2:189565370, MAF = 0.16853, p = 5.2×10−4). We also found several variants in AC105411.1, TJP1 and DCC that were close to genome-wide significance level. Further analysis will be carried out on the cloud-based platform provided by NHLBI BioData Catalyst using data from all the four cohorts to validate the previous analysis and expand to related phenotype such as transferrin, iron-overload status. Discussion: In this study we identified common and rare variants that associate with serum ferritin concentration. The results from this pilot study point to novel gene variants that might contribute to iron overload in SCD patients and serve as new biomarkers. Future analysis is needed to determine whether the identified variants can also help with therapeutics and outcome prediction for early stages of SCD-associated iron overload. Our findings will be useful for the future treatment of SCD patients and design of novel SCD therapeutics. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, and 1R01HL125005). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosures Gordeuk: Imara: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Telen:CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics Inc.: Consultancy.

scholarly journals Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3542-3542 ◽  
Author(s):  
Natalia Scaramellini ◽  
Carola Arighi ◽  
Alessia Marcon ◽  
Dario Consonni ◽  
Elena Cassinerio ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Liver Function ◽  
Iron Overload ◽  
Board Of Directors ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Published Data ◽  
Iron Chelation Therapy ◽  
Iron Intake ◽  
Advisory Committees

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p&lt;0.001) and for SF&lt;500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT&gt; 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value &lt; 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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.

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.

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