journal presentation journal club

1. JOURNAL CLUB
 17 July 2019
Dr KM Parakrama
Reg WD 15 A2

2. Effects of deferasirox dose and decreasing serum
ferritin concentrations on kidney function in
paediatric patients: an analysis of clinical laboratory
data from pooled clinical studies
Steven T Bird, Richard S Swain, Fang Tian, Olanrewaju O Okusanya, Peter
Waldron, Mona Khurana, Elizabeth L Durmowicz, Yong Ma, Jacqueline M Major,
Kate Gelperin
Lancet Child Adolesc Health 2018
Published Online November 16, 2018

3. Introduction
 Chronic red blood cell transfusion causes transfusional haemosiderosis.
 It can have clinical consequences on the liver, heart, and endocrine organs.
 Deferasirox is an orally active iron chelator approved for the treatment of
chronic iron overload due to blood transfusions in patients aged 2 years and
older.
 For non-transfusion-dependent thalassaemia syndromes in patients aged 10
years and older
 Chelation therapy with deferasirox can cause serious adverse reactions,
including renal failure, hepatic failure, and gastrointestinal haemorrhage.

4.  Monitoring of renal and hepatic function at least monthly to mitigate
deferasirox-associated risks.
 Despite these recommendations, cases of deferasirox toxicity in paediatric
patients have been published and reported through post-marketing
surveillance.
 Reports suggest that increase risk with low accumulated body iron burden,
high deferasirox dose, or an interaction between these two factors.

5. Objectives
 To investigate the effects of deferasirox dose and serum ferritin
concentrations, separately and combined, on kidney function,
 To examine the relationship between impaired kidney function and
deferasirox plasma concentrations
 To identify modifiable risk factors for severe deferasirox toxicity in paediatric
patients

6. Methods
 Study design and participants-
 Case-control analysis using pooled data from ten clinical studies.
 Including eight interventional clinical trials and two non-interventional
studies with prospective protocol-based collection of clinical laboratory data.

7.  1st set of data-clinical and laboratory data for paediatric patients aged 2–15
years who had a diagnosis of transfusion-dependent thalassaemia and were
receiving deferasirox
 2nd dataset included data on the minimum plasma concentration (Cmin) of
deferasirox from paediatric patients aged 2–15 years with the broader
transfusional iron overload indication
 Data on estimated glomerular filtration rate (eGFR) and dose-normalised Cmin
were obtained from three clinical studies with deferasirox plasma
concentration data
 Analysis included data for the deferasirox dispersible tablet and film-coated
tablet or granule formulations

8. Inclusion criteria
 Have had a baseline visit and at least one follow-up visit
 Deferasirox dose and serum creatinine and serum ferritin concentrations were
available

11. Data Collection
 eGFR from the patient’s serum creatinine measurement at each study visit
was calculated
 Patients with a baseline eGFR of 100 mL/min per 1·73 m² or more were
considered to have an acute kidney injury (AKI) episode when their eGFR was
90 mL/min per 1·73 m² or less
 Threshold for onset of renal dysfunction defined by the FDA’s Guidance on
pharmacokinetics in patients with impaired renal function11 and the National
Kidney Foundation
 Patients with a baseline eGFR of less than 100 mL/min per 1·73 m² were
considered to have an AKI episode when the eGFR decreased from baseline by
25% or more

12.  Based on RIFFLE criteria
 or reached 60 mL/min per 1·73 m² or less, whichever occurred first
 Each patient could contribute only one case to the analysis
 Pool of controls available for matching consisted of all patient visits with an
eGFR of 120 mL/min per 1·73 m² or more
 It was to select a control population with normal kidney function and exclude
patient visits during periods when kidney function was diminishing but the
eGFR threshold for AKI had not been reached
 Control visits were matched on age (±1 year and within stratifications of 2–6
years and 7–15 years), sex, study site, and time since drug initiation (±1
month)
 The effect of deferasirox dose on AKI was evaluated for each 5 mg/kg per day
increment in deferasirox above the typical starting dose of 20 mg/kg per day
 Elevated dose was defined as more than 25 mg/kg per day
 High dose as more than 30 mg/kg per day

13.  Serum ferritin was recorded at monthly intervals for most patients
 The effect of serum ferritin on AKI was evaluated per 250 μg/L decrease
starting from 1250 μg/L
 Low serum ferritin was defined as less than 1000 μg/L

14. Data Analysis
 Separate models evaluated the effect of deferasirox dose and the effect of
serum ferritin on AKI.
 A subsequent model included the main effects for high-dose deferasirox and
low serum ferritin
 Secondary analyses evaluated risk for AKI within prespecified stratifications
on age (2–6 years and 7–15 years).
 Modification of this effect by age and body surface area were estimated using
linear mixed effects models

15. Results
 1213 paediatric patients with transfusiondependent thalassaemia enrolled in
the ten studies
 162 patients with AKI episodes were identified and matched to 621 control
visits from seven studies
 Patients with AKI had a mean 50·2% (SD 15·5) eGFR decrease from baseline
 Compared with a 6·9% (SD 29·8) eGFR decrease in controls
 Baseline eGFR of less than 100 mL/min per 1·73 m² was observed in only four
cases
 Among the 162 patients with AKI, 91 (56%) had a dose increase in the 30 days
before the AKI event

16.  The risk estimate for high-dose deferasirox increased as the severity of kidney
injury increased from eGFR 100 mL/min per 1·73 m² or less
 An increased risk for AKI was also observed per 250 μg/L decrease in serum
ferritin, starting from 1250 μg/L
 High-dose deferasirox resulted in significantly increased risk for AKI in
paediatric patients when serum ferritin was low (<1000)
 However, the risk of AKI was also slightly increased when serum ferritin was at
least 1000 μg/L suggesting dose-related nephrotoxicity
 The effect of low serum ferritin was not significant among patients not
receiving high-dose deferasirox
 Risk for AKI with high-dose deferasirox was greater in patients aged 2–6 years
than in those aged 7–15 years.
 Risk for AKI with serum ferritin less than 1000 μg/L was higher for patients
aged 2–6 years than those aged 7–15 years.
 No significantly different risk in children aged 2–6 years versus those aged 7–
15 years for high-dose deferasirox and low serum ferritin

17.  Most patients with AKI (155 [96%] of 162) had a documented recovery to eGFR
of more than 100 mL/min per 1·73 m².
 Seven (4%) patients permanently dropped out of their study after their initial
AKI episode.
 After the initial AKI episode, deferasirox treatment was discontinued in 11
(7%) of 162 patients, and the dose was decreased in 12 (7%).
 95 (59%) of 162 patients with AKI had a documented recovery within 28 days
 Among the 155 patients who recovered, 62 (40%) had a subsequent episode of
AKI
 A significant relationship was observed between eGFR and dose-normalised
Cmin, where decreases in eGFR were associated with higher deferasirox
plasma concentrations
 Smaller baseline body surface area and younger age were also associated with
higher Cmin.

21. Strengths
 Large sample size.
 Included several age groups.
 This study is the first to evaluate risk for AKI through pooling laboratory data
from paediatric patients in deferasirox clinical studies.
 Multiple published reports describe deferasirox associated proximal renal
tubular injury, but reports of deferasirox-associated glomerular dysfunction
are not as well described.
 Included studies required monitoring of serum creatinine, serum ferritin, and
Cmin for evaluation of renal function.

22.  Chronic anaemia in this population can also lead to compensatory changes in
renal blood flow, causing glomerular hyperfilteration.
 The clinical trials dataset had a mean eGFR at trial enrolment of 194·7
mL/min per 1·73 m² whereas children without kidney disease have been
reported to have a mean GFR of 127 mL/min per 1·73 m²
 Matching within study site was included to account for different laboratory
assay methods by site or differences in practice by geographical location.

23. Weaknesses
 The increases in serum creatinine in our study, which led to decreased eGFR
values, might have been due to decreased glomerular filtration of creatinine,
decreased tubular secretion of creatinine, or both.
 The pooled data did not include other markers of glomerular and tubular
function to allow these distinctions.
 Other potential causes of AKI were not explored in the analysis,
 But inspection of adverse event reports from the clinical studies did not
identify other important causes of kidney injury.

24. Discussion
 Identified increased risk for AKI in paediatric patients receiving high-dose
deferasirox during periods where their iron burden was low.
 Transfusion-dependent paediatric patients with thalassaemia with low serum
ferritin concentrations received high-dose deferasirox, a combined effect of
both risk factors was observed
 Resulting in a 4·47-times increased risk for AKI
 High dose deferasirox in the context of a body iron burden approaching
normal physiological concentrations can deprive tissues of the iron required
for normal organ function
 Over chelation is a potential contributing factor for serious and fatal toxicity,
including kidney and liver failure

25.  Decrease in eGFR was associated with increased dose-normalised deferasirox
plasma concentrations.
 This unexpected finding emphasises the importance of monitoring kidney
function during therapy with deferasirox, even though it is predominantly
excreted in the faeces.
 Increases in deferasirox concentration can exacerbate kidney injury, causing a
cycle of escalating toxicity.
 Patients with smaller body surface area and younger age had a significantly
higher deferasirox plasma concentrations at a given eGFR than did those with
larger body surface area and older age.
 Risk estimates for AKI were also numerically higher among patients aged 2–6
years than among those aged 7–15 years.
 Dose-related nephrotoxicity observed with deferasirox is generally reversible
when treatment is interrupted or discontinued.
 Nearly all patients with AKI in the current study recovered to their baseline
renal function.

26.  16 children developed a pattern of kidney injury with more than four total AKI
episodes.
 Transfusional iron loading and chelators-induced removal of iron are not
uniform across organs.
 Discrepant rates of iron loading and removal between organs might be a
component of the apparent increased vulnerability of kidneys to over
chelation.
 Liver iron concentration is the reference standard to guide chelation therapy.
 Routine liver iron concentration testing is expensive and not readily available.
 Studies have consistently found a significant correlation between serum
ferritin and liver iron concentrations among patients with thalassaemia.
 eGFR can provide a useful indicator of kidney function over time when
measured sequentially.
 Overestimation of true GFR is a possibility for patients with low baseline
serum creatinine values because of reduced muscle mass or malnutrition from
their chronic disease.

27. Conclusion
 Deferasirox causes AKI in a dose dependent manner in a dynamic process with
lower serum ferritin concentrations.
 Physicians should use the lowest possible deferasirox dose to establish and
maintain an acceptable iron burden.
 Dose reductions should be considered with consecutive serum ferritin values
of less than 1000 μg/L.
 Patients with pre-existing renal disease, declining renal function, or a recent
AKI episode might be especially susceptible to a cycle of repeated kidney
injury.
 Acute illnesses might also increase the risk of AKI.

28.  Deferasirox should be interrupted during episodes of declining renal function
or acute illnesses, which can cause volume depletion.
 Eg-:vomiting, diarrhoea, or prolonged decreased oral intake.
 Even small decreases in eGFR can result in increases in deferasirox
exposure.
 Specially in young patients with small body surface area.
 Consistent monitoring of kidney function (including eGFR) and serum ferritin
concentrations is needed to guide dosing decisions.

29. THANK YOU!