LAUSR

To the Editor: Renal adverse events (AE) and increases in serum creatinine (SCr) have been reported in patients with transfusional hemosiderosis treated with deferasirox. Since the core registration trials, various extension and long-term observational studies have been conducted in pediatric and adult populations. These studies have described the reversible, non-progressive nature of SCr increases and confirmed the overall acceptable renal safety profile of deferasirox. Given the chronic nature of treatment, especially in children with congenital anemias, a longer follow-up was thought opportune to demonstrate the absence of late or cumulative effects of deferasirox in real treatment practice. Italian sites enrolled 34% of the patients across the registration studies, and many of these patients have since then been followed up by the same physicians. This allowed us to conduct a retrospective chart review of SCr values, other renal parameters, and renal AEs in patients on iron chelation therapy for up to 13 years. To minimize selection bias, the study set out to enroll all patients who were treated with at least one dose of deferasirox during the registration trials and had at least one post-baseline assessment of SCr. All available charts had an equal chance of selection but the first SCr, urinary protein, and urinary creatinine values available at the same visit were collected quarterly. Of the 282 patients analyzed, more than 90% were observed for at least seven years following the registration studies. At quarter 1, 65 patients (23%) were less than 18 years of age and 217 patients (76%) were 18 years or older. b-Thalassemia was by far the most common underlying disease (n5264), followed by myelodysplastic syndromes (n59), sickle cell disease (n57), and other anemias (n52). As commonly occurs in real world practice, most patients were not treated with the same chelator since the registration studies but were exposed to various chelating agents including deferasirox. Baseline and worst value of SCr recorded during the registration studies, as well as the quarterly trend over the retrospective period are shown in Figure 1. Mean baseline value was 53.39613.45 lmol/L (range 20.35–87.96 lmol/L), while the worst value was on average 79.73620.19 lmol/L (range 35.40–156.50 lmol/L). During the retrospective period, mean/median SCr values were slightly higher than baseline but lower than worst value, with a stable quarterly trend (around 60 lmol/L in mean) until quarter 43, when the number of patients began to drop considerably and mean/median values started fluctuating. A subgroup analysis assessed SCr in patients (n598) treated with only deferasirox during the retrospective period. Mean value was 50.05613.69 mmol/L at baseline and stable throughout the retrospective period, with mean values between 60 and 65 mmol/L, corresponding to a 15%-20% increase from baseline at most quarters. The SCr trend was traced in a subgroup made up of patients (n5197) with renal AEs or confirmed, notable renal laboratory values during the registration studies. Mean SCr at baseline was 53.236 13.72 lmol/L (range 26.10–87.96 lmol/L), and mean worst value 82.95621.11 lmol/L (range 41.50–156.50 lmol/L). Mean/median values were then steady over time, higher than baseline but lower than worst value, and about the same as values for the full Safety Set (around 62 lmol/L vs. 60 lmol/L), indicating that renal AEs occurring during the registration studies did not provoke irreversible or progressive long-term effects on renal function. Although data for urinary protein, urinary creatinine, and creatinine clearance were often missing, these renal parameters also appeared to remain steady over the retrospective period, with values below the worst value reported in the registration studies. During the retrospective period, renal AEs regardless of treatment relations were reported in 86/282 (30.5%) patients. The most common were nephrolithiasis (10.99% of patients) and renal colics (9.93%), followed by abnormal urine protein/creatinine (UPCR) ratio, abnormal/ increased SCr, and proteinuria. At least one serious adverse event (SAE) was reported for eight patients (2.84%) (increased SCr, acute kidney injury, hematuria, hydronephrosis, renal colic, renal failure, and urethral stenosis). No causal relationship was suspected between the events and treatment with deferasirox. Suspected deferasirox-related renal AEs were reported in 33 patients (11.70%). Proteinuria, abnormal/increased UPCR, and increased blood creatinine were the most frequently reported drug-related events. None of these events was serious but four were considered of severe intensity: increase of UPCR (n52), proteinuria, and glycosuria. In most cases, deferasirox was temporarily interrupted or dosage was adjusted and no further action was required. Five (5) patients (1.77%) did however discontinue treatment permanently. No cases of acute renal failure or of end stage renal disease were reported during the retrospective period. The one case of “acute kidney injury” mentioned previously as an SAE occurred during acute pancreatitis.