Follow‐up report on the 2‐year cardiac data from a deferasirox monotherapy trial
Authors: John C. Wood, Tara Glynos, Alexis Thompson, Patricia Giardina, Paul Harmatz, Barinder P. Kang, Carole Paley, Thomas D. Coates
Journal: American Journal of Hematology (2010)

The trial CICL670AUS04 was a single arm, open-label study of the cardiac efficacy of 18 months of deferasirox monotherapy [1]. Cardiac response in this study was related to the degree of liver siderosis. Patients with mild to moderate liver siderosis improved their cardiac T2* while more severely siderotic patients did not, regardless of initial cardiac iron burden. In this letter, we report 2-year data in those patients who completed a 6-month extension phase (N = 10). Cardiac and liver iron improved steadily during the 24-month period, with final cardiac T2* and LIC improving 37% and 27%, respectively, in this cohort. Serum ferritin and LVEF were not statistically different at any time-point. When the extension phase (18–24 months) was considered in isolation, serum ferritin, liver iron concentration, and left ventricular ejection fraction were nearly identical to 18 month results. Despite this, cardiac T2* continued to trend higher, increasing 12.7% from 9.5 ms to 10.7 ms (P = 0.06). Thus defersirox continued to demonstrate cardiac efficacy in patients with mild to moderate hepatic siderosis throughout 2 years of therapy. Table I summarizes changes in serum ferritin, LIC, T2*, and LVEF over the entire study interval for the 10 patients completing extension; significant changes have bold text. In general, differences between mean and median values increased over time for indices of iron burden, reflecting the dichotomous response to the drug described previously [1]. Median ferritin and LIC improved progressively, consistent with favorable response observed in mild to moderately iron overloaded subjects. In contrast, mean serum ferritin and LIC were dominated by changes of a few very heavily iron overload subjects who were relatively refractory to treatment. Based on the inclusion/exclusion criteria for extension (see methods), there was a slight bias toward favorable response to the drug; four responders (>14.7% improvement over 18 months) were ineligible versus six nonresponders. Of the ten patients completing extension, six were 18-month cardiac responders and four were cardiac nonresponders. Responders had lower serum ferritin (2854 ± 1098 ng/ml vs. 5323 ± 3502 ng/ml), LIC (13.1 ± 5.3 mg/g vs. 31.2 ± 22.6 mg/g), and higher T2* (8.3 ms vs. 7.0 ms); these disparities, although large, did not reach statistical significance because of the small sample size and high intersubject variability. LVEF (63.7 ± 6.0% vs. 64.8 ± 4.3%) was quite similar in the two groups. Figure 1 demonstrates the complete cardiac T2* trajectories for all 10 extension participants. Eighteen month cardiac responders are indicated by solid lines and cardiac nonresponders by the dashed lines. In general, patients maintained their prior trajectories. Compared with 18 months, six patients improved, two were unchanged, and two worsened. Plot of cardiac T2* as a function of time in 10 patients who completed 24 months of deferasirox monotherapy. 18-month cardiac responders are depicted by the solid line and non responders by the dotted line. Two individual trajectories are of interest. The first trajectory (arrow) represents a patient who started with a liver iron of 10.6 and a T2* of 5.8 ms. Despite downward trend in his liver iron, his cardiac T2* failed to improve over 18 months. Between 18 and 24 months, his LIC improved from 6 mg/g to 3.8 mg/g and cardiac T2* increased from 5.4 to 8.1 ms. Thus late improvement in cardiac T2* may occur, once somatic stores are sufficiently depleted, consistent with a competitive chelation process. The second patient (asterisk) nearly doubled their cardiac T2* (9.7 ms to 17.4 ms) over the first 6 months. However, T2* progressively declined thereafter (reaching 14.4 ms at 24 months) despite maintaining negative liver iron balance (24 month LIC 3.8 mg/g dry weight of liver). Although an overall increase in cardiac T2* from 9.7 ms to 14.4 ms over 2 years is clinically acceptable, this example demonstrates that negative liver iron balance does not guarantee successful cardiac chelation and reinforces the need for cardiac MRI surveillance. This patient admitted to missing 2–3 chelator doses per week. This example, while anecdotal, suggests incomplete compliance with high dose deferasirox may lower hepatic iron concentration without successful control of cardiac iron burden. In summary, the 2-year US04 data support the use of deferasirox monotherapy in patients with mild to moderate hepatic siderosis and normal heart function, with cardiac T2* improving 37% over 2 years. However, careful monitoring of patient compliance and cardiac T2* remains imperative because successful control of somatic iron stores does not guarantee sustained improvements in cardiac T2*. Patients were offered participation in the study extension if their T2* was less than 20 ms at week 77, there was T2* and/or LIC improvement of 25% from baseline and ventricular function was normal. 12 out of 22 patients qualified for extension, 11 participated and 10 completed the extension. Reasons for subject ineligibility were inadequate response over 18 months in six subjects and T2* > 20 ms in four subjects. Other experimental methods have been described in considerable detail in the 18-month report and are not repeated here [1]. The authors thank Anne Nord, RN, Susan Carson, PNP, Kelly Verel, Dena Fasheh, Elizabeth Evans, Jacqueline Madden, PNP, Matthew Cham, MD, and Matthew Herz for their help in patient recruitment and management. They also appreciate the help of Kevin Mennitt, MD, Barbara Bettencourt, and Cindy Rigsby, MD, for their assistance in MRI measurements as well as Ghulam Warsi, PhD, for his statistical assistance. J.W. and T.C. designed the experiment, collected data, analyzed and interpreted the data, and wrote the manuscript. A.T., P.H., and P.G. collected data and wrote the manuscript. B.K., C.P., and T.G. designed the experiment, analyzed and interpreted data and wrote the manuscript. All authors have reviewed and approved the final version. John C. Wood*, Tara Glynos , Alexis Thompson , Patricia Giardina§, Paul Harmatz¶, Barinder P. Kang , Carole Paley , Thomas D. Coates**, * Department of Pediatrics and Radiology, Divisions of Cardiology and Radiology, Children's Hospital of Los Angeles, CA, Novartis Pharmaceuticals Corporation, Morristown, NJ, Department of Pediatrics, Division of Hematology, Children's Memorial Hospital, Chicago, IL, § Department of Pediatrics, Division of Hematology, Weill Cornell Medical Center, New York, NY, ¶ Department of Pediatrics, Division of Gastroenterology, Children's Hospital Oakland, CA, ** Department of Pediatrics, Division of Hematology, Children's Hospital of Los Angeles, CA.