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
Authors: Gattermann Norbert , Greenberg Peter L. , Urabe Akio , Habr Dany , Kpamegan Euloge E. , Porter John B. 
Published: October 2019

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.