Comparison of LIC Obtained from Biopsy, BLS and R2-MRI in Iron Overloaded Patients with β-Thalassemia, Treated with Deferasirox (Exjade®, ICL670).

Abstract Chelation therapy for patients with transfusional hemosiderosis is guided by the degree of iron overload and ongoing transfusion requirements; liver iron concentration (LIC) is one tool for measuring current iron burden. During the clinical development of the novel oral iron chelator deferasirox, LIC was measured in subcutaneous liver biopsy samples, but also non-invasively by biomagnetic liver susceptometry (SQUID-BLS) and magnetic resonance imaging (R2-MRI: FerriScan®). These methods were compared in a substudy of a large, open-label, randomized Phase III study in 586 β-thalassemia patients with transfusional hemosiderosis; the study evaluated the efficacy and safety of long-term deferasirox and deferoxamine treatment. 48 patients (aged 17–35 yrs) gave informed consent for adding BLS and MRI assessments (baseline, 6 and 12 months) to the biopsy assessments (baseline and 12 months) of the main study. At baseline, 47 patients were assessed by BLS and biopsy, 45 by R2-MRI; at 6 months, 42 by BLS and R2-MRI; at 12 months, 41 by BLS and R2-MRI, 39 by biopsy. BLS was performed and evaluated locally at 3 centers in Hamburg, Turin and Oakland. MR images were recorded at 4 centers in Hamburg, Turin, Stanford and Los Angeles and were analyzed centrally. Data from BLS and R2-MRI remained blinded until study completion. LIC from biopsies was determined by AAS from extracted paraffin blocks in a central laboratory and used as the standardized reference method. LIC was expressed as mg/g dry weight for all methods: for BLS, a wet-to-dry weight conversion factor of 3.3 was applied, while MRI was calibrated against fresh freeze-dried liver biopsies. The relationship between BLS or R2-MRI with biopsy measurements was modeled by linear regression after log-transformation of the data. To account for the correlation between baseline and post-baseline measurements of the same patient, mixed-effects models were fitted. On average, the LIC data obtained from BLS and biopsy were related by a factor of 0.46 (95% CI: 0.32, 0.67). With R2-MRI assessment of LIC vs biopsy, the factor was 0.72 (95% CI: 0.54, 0.97). BLS and R2-MRI measurements could not be related appropriately by a factor. Overall, LIC from biopsy was generally larger than that obtained from BLS; R2-MRI measurements fell in-between biopsy and BLS. Differences are caused in part by the variability in the wet-to-dry weight ratio relating in vivo with in vitro methods. In conclusion, LIC data from 3 independent methods were correlated but not equivalent. It is therefore important that for an individual patient, a single method is consistently used under standardized conditions.

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Deferasirox (Exjade®, ICL670) Demonstrates Iron Chelating Efficacy Related to Transfusional Iron Intake in Pediatric Patients.

Blood ◽

10.1182/blood.v106.11.2692.2692 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2692-2692 ◽

Cited By ~ 4

Author(s):

C. Kattamis ◽

Y. Kilinc ◽

S. Fattoum ◽

A. Ferster ◽

D. Gallisai ◽

...

Keyword(s):

Serum Ferritin ◽

Safety Profile ◽

Pediatric Patients ◽

Iron Concentration ◽

Phase Iii ◽

Average Dose ◽

Iron Intake ◽

Open Label ◽

Liver Iron ◽

Transfusion Requirements

Abstract Chelation therapy is the conventional treatment for transfusional iron overload, which leads to complications in the heart, liver and endocrine glands. A 1-year, open-label, multicenter, Phase III study compared the investigational, once-daily, oral iron chelator deferasirox (DSX) with deferoxamine (DFO) in adult and pediatric β-thalassemia patients aged ≥ 2 years. Patients with liver iron concentration (LIC) of 2–3, >3–7, >7–14 and >14 mg Fe/g dw were randomized to receive daily DSX 5, 10, 20 and 30 mg/kg or DFO 20–30, 25–35, 35–50 and ≥ 50 mg/kg, respectively. In total, 586 patients received treatment; 299 (51%) were aged <16 years, of whom 154 were treated with DSX. Baseline demographics and changes in LIC and serum ferritin after 1 year of treatment are shown in the table; data are presented as mean ± SD (standard deviation). DSX produced a fall in LIC in all age groups. A more moderate reduction in LIC occurred in patients aged <6 years despite the administration of an average dose of 21.9 mg/kg in this subgroup; these patients had the highest mean transfusional iron intake. The results strongly suggest that transfusional iron intake is the major factor in determining response and should be considered carefully when dosing iron chelators in children. In those with high transfusion requirements, a dose of 30 mg/kg may be considered. DSX DFO EOS = end of study; SF = serum ferritin; aAll patients with a baseline and EOS LIC assessment Age at baseline, years <6 (n=30) 6–11 (n=67) 12–15 (n=57) <6 (n=28) 6–11 (n=68) 12–15 (n=49) Female: male, n 12:18 35:32 35:22 9:19 33:35 30:19 Average daily dose, mg/kg 21.9 ± 7.61 21.1 ± 8.49 18.0 ± 9.00 43.6 ± 9.17 42.5 ± 9.11 43.5 ± 9.62 Baseline LICa, mg Fe/g dw 13.2 ± 7.4 15.2 ± 10.6 12.4 ± 10.5 12.6 ± 6.0 13.2 ± 9.4 13.3 ± 10.4 EOS LICa, mg Fe/g dw 12.1 ± 4.4 11.1 ± 7.7 9.6 ± 7.0 8.8 ± 3.8 10.6 ± 7.4 9.8 ± 6.6 Baseline SF, ng/mL 2479 ± 843 3058 ± 1834 2813 ± 1567 2260 ± 874 2745 ± 1633 2847 ± 1507 EOS SF, ng/mL 2791 ± 1066 2710 ± 1526 2787 ± 1494 1774 ± 769 2439 ± 1356 2495 ± 1529 Transfusional iron intakea, mg/kg/day 0.48 ± 0.11 0.43 ± 0.09 0.37 ± 0.10 0.47 ± 0.12 0.44 ± 0.12 0.40 ± 0.10 DSX was well tolerated in children as young as 2 years of age at all dose levels, with a safety profile similar to that observed in adults. The most common adverse events (AEs) with a suspected relationship to DSX were abdominal pain, nausea, vomiting, diarrhea and skin rash. Of 154 pediatric patients who received DSX, 5 (3.2%) discontinued due to suspected drug-related AEs. There was no treatment-related neutropenia, agranulocytosis or arthralgia. Sexual development proceeded normally with no differences between the treatment groups. DSX has a safety profile that is compatible with long-term use in children as young as 2 years and is generally well tolerated at doses as high as 30 mg/kg in these heavily transfused patients.

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Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias

Acta Haematologica ◽

10.1159/000381893 ◽

2015 ◽

Vol 134 (4) ◽

pp. 233-242 ◽

Cited By ~ 9

Author(s):

Yutaka Kohgo ◽

Akio Urabe ◽

Yurdanur Kilinç ◽

Leyla Agaoglu ◽

Krzysztof Warzocha ◽

...

Keyword(s):

Aplastic Anemia ◽

Myelodysplastic Syndromes ◽

Iron Concentration ◽

Dry Weight ◽

Japanese Patients ◽

Efficacy And Safety ◽

Liver Iron Concentration ◽

Open Label ◽

Liver Iron ◽

Therapeutic Goals

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10-40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was -10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and -13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

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Phase III Evaluation of Once-Daily, Oral Therapy with ICL670 (Exjade®) Versus Deferoxamine in Patients with β-Thalassemia and Transfusional Hemosiderosis.

Blood ◽

10.1182/blood.v104.11.3619.3619 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3619-3619 ◽

Cited By ~ 4

Author(s):

Maria Cappellini ◽

Mohamed Bejaoui ◽

Silverio Perrotta ◽

Leyla Agaoglu ◽

Antonios Kattamis ◽

...

Keyword(s):

Quantum Interference ◽

Safety Data ◽

Study Drug ◽

Dry Weight ◽

Phase Iii ◽

Outcome Variable ◽

Efficacy And Safety ◽

Open Label ◽

Liver Iron ◽

Once Daily

Abstract ICL670 (deferasirox) is an investigational once-daily oral iron chelator that has demonstrated the ability to induce sustained, clinically relevant reductions in liver iron content (LIC) in heavily transfused patients with β-thalassemia and iron overload. The efficacy and safety of ICL670 is being assessed in a multicenter, randomized, open-label Phase III study in comparison with deferoxamine (DFO) in patients aged ≥2 years with β-thalassemia and transfusional hemosiderosis. Between March and November 2003, 587 patients began treatment (296 on ICL670; 291 on DFO) in the following 12 countries : Italy (200), Turkey (87), Tunisia (68), US (48), Greece (46), Germany (27), Argentina (24), Belgium (24), Brazil (20), UK (18), Canada (13) and France (12). Based on LIC at baseline (2–3, >3–7, >7–14 and >14 mg Fe/g dw), patients were randomized in a 1:1 ratio to receive either oral ICL670 once daily at doses of 5, 10, 20 or 30 mg/kg, respectively, or subcutaneous DFO at doses of 20–60 mg/kg/day for 5 days/week. Treatment was for one year initially, to be followed by an extension phase during which patients randomized to DFO may switch to ICL670. LIC, the primary outcome variable, was assessed at baseline by liver biopsy or, in some children, non-invasively by magnetic susceptometry using a Superconducting QUantum Interference Device (SQUID). LIC will be reassessed after 12 months of therapy in each patient using the same methodology as at baseline. Liver biopsies are analyzed at a single center (Rennes, France) and SQUID assessments are performed in 3 centers (Turin, Italy; Hamburg, Germany; Oakland, US). At baseline, median (25–75th percentiles) LIC was 13.0 mg Fe/g dw (7.2–21.0) by biopsy and 5.6 (4.0–7.7) in those patients assessed by SQUID. Total body iron balance will be assessed to determine the relative chelation efficacies of ICL670 and DFO. A summary of patient demographics and baseline characteristics (median values or no. of pts) is given in the table. ICL670 has been well tolerated with mild, transient gastrointestinal complaints as the main AEs with a suspected relationship to study drug. As of May 2004, 8 patients on ICL670 and 2 on DFO had discontinued therapy due to AEs. The key efficacy and safety data from the initial 12 months of therapy for all randomized patients will be available late November 2004. Treatment group (by initial dose) ICL670 (n=296) Deferoxamine (n=291) 10 mg/kg n = ≤ 94 20 mg/kg n = 83 30 mg/kg n = 119 <35 mg/kg n = 51 35-<50 mg/kg n = 119 ≥ 50 mg/kg n = 121 Age (yrs) median 15 15 15 15 14 17 No. of pts 2 - <16 years 49 44 60 26 63 56 No. of ≥ pts 16 yrs 45 39 59 25 56 65 No. of males/females 44/50 41/42 54/65 32/19 50/69 61/60 LIC (mg Fe/g dry weight) 4.7 10.6 21.8 4.5 9.1 19.5 No. of pts with biopsy/SQUID* 60/34 69/14 117/0* 36/15 93/26 119/2 Serum ferritin (ng/ml) 1881 1954 3250 1546 2037 2383

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SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis

Journal of Clinical Oncology ◽

10.1200/jco.2017.73.4418 ◽

2017 ◽

Vol 35 (34) ◽

pp. 3844-3850 ◽

Cited By ~ 85

Author(s):

Ruben A. Mesa ◽

Jean-Jacques Kiladjian ◽

John V. Catalano ◽

Timothy Devos ◽

Miklos Egyed ◽

...

Keyword(s):

Kinase Inhibitor ◽

Janus Kinase ◽

Phase Iii ◽

Similar Proportion ◽

Transfusion Rate ◽

Spleen Volume ◽

Open Label ◽

Transfusion Requirements ◽

Symptom Response ◽

Grade 3

Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

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Liver Iron Concentration Assessed by SQUID Biosusceptometry Compared to Heat-dried Liver Biopsy: A Blinded Study.

10.21203/rs.3.rs-1135845/v1 ◽

2021 ◽

Author(s):

Marcela Weyhmiller ◽

Zahra Pakbaz ◽

John Butz ◽

Ellen Fung ◽

Douglas Paulson ◽

...

Keyword(s):

Liver Biopsy ◽

Tissue Sample ◽

Iron Concentration ◽

Weight Ratio ◽

Dry Weight ◽

Liver Iron Concentration ◽

Fresh Tissue ◽

Liver Iron

Abstract Objective Biomagnetic liver susceptometry (BLS) is a noninvasive method to quantify liver iron concentration (LIC). Here we report our findings from a prospective study which validates in vivo LIC from a SQUID biosusceptometer by in vitro LIC in fresh tissue and paraffin-embedded biopsies from patients at risk for iron overload.Materials and Methods LIC was measured by BLS and biopsy. LIC by biopsy were measured in 40 dry weight fresh tissue and paraffin-embedded liver biopsy samples. LIC from biopsies and total iron scores from histology were compared to biosusceptometry. In addition, the wet-to-dry weight ratio was determined.Results Liver iron concentrations measured by BLS and in 40 fresh tissue biopsies were related by a factor of 6.0 ± 0.2 (r2 = 0.88). Similar results were obtained from comparisons with deparaffinized biopsies (6.6±0.3, r2=0.87) and histology (6.7±1.3, r2=0.47). In contrast, a mean wet-to-dry weight ratio of 4.1 ± 0.7 was achieved from biopsies immediately weighed after the biopsy procedure.ConclusionLIC derived from two independent measures, the historical biopsy gold standard and biosusceptometry, were highly correlated. When comparing biosusceptometry with wet weight biopsies, the liver tissue sample size is critical.

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Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label, noninferiority study

Blood Advances ◽

10.1182/bloodadvances.2021004938 ◽

2021 ◽

Author(s):

Janet L Kwiatkowski ◽

Mona Hamdy ◽

Amal El Beshlawy ◽

Fatma S.E. Ebeid ◽

Mohammed Badr ◽

...

Keyword(s):

Iron Overload ◽

Least Squares ◽

Iron Concentration ◽

Dry Weight ◽

Iron Chelator ◽

Analysis Of Covariance ◽

Efficacy And Safety ◽

Open Label ◽

Liver Iron ◽

Transfusion Therapy

Many people with sickle cell disease (SCD) or other anemias require chronic blood transfusions, which often causes iron overload and requires chelation therapy. The iron chelator deferiprone is often used in individuals with thalassemia syndromes, but data in patients with SCD are limited. This open-label study (NCT02041299) assessed the efficacy and safety of deferiprone in patients with SCD or other anemias receiving chronic transfusion therapy. A total of 228 patients (mean age: 16.9 [range 3-59] years; 46.9% female) were randomized to receive either oral deferiprone (n = 152) or subcutaneous deferoxamine (n = 76). The primary endpoint was change from baseline at 12 months in liver iron concentration (LIC), assessed by R2* magnetic resonance imaging (MRI). The least squares mean (standard error) change in LIC was −4.04 (0.48) mg/g dry weight for deferiprone vs −4.45 (0.57) mg/g dry weight for deferoxamine, with noninferiority of deferiprone to deferoxamine demonstrated by analysis of covariance (least squares mean difference 0.40 [0.56]; 96.01% confidence interval, −0.76, 1.57). Noninferiority of deferiprone was also shown for both cardiac T2* MRI and serum ferritin. Rates of overall adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to withdrawal did not differ significantly between the groups. AEs related to deferiprone treatment included abdominal pain (17.1% of patients), vomiting (14.5%), pyrexia (9.2%), increased alanine transferase (9.2%) and aspartate transferase levels (9.2%), neutropenia (2.6%), and agranulocytosis (0.7%). The efficacy and safety profiles of deferiprone were acceptable and consistent with those seen in patients with transfusion-dependent thalassemia.

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