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Deferasirox for managing transfusional iron overload in people with sickle cell disease

  1. Joerg J Meerpohl1,*,
  2. Lisa K Schell1,
  3. Gerta Rücker2,
  4. Edith Motschall3,
  5. Nigel Fleeman4,
  6. Charlotte M Niemeyer5,
  7. Dirk Bassler6

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 27 MAY 2014

Assessed as up-to-date: 6 MAY 2014

DOI: 10.1002/14651858.CD007477.pub3


How to Cite

Meerpohl JJ, Schell LK, Rücker G, Motschall E, Fleeman N, Niemeyer CM, Bassler D. Deferasirox for managing transfusional iron overload in people with sickle cell disease. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD007477. DOI: 10.1002/14651858.CD007477.pub3.

Author Information

  1. 1

    Medical Center - University of Freiburg, German Cochrane Centre, Freiburg, Germany

  2. 2

    Medical Center - University of Freiburg, Department of Medical Biometry and Medical Informatics, Freiburg, Germany

  3. 3

    Medical Center - University of Freiburg, Center for Medical Biometry and Medical Informatics, Freiburg, Germany

  4. 4

    University of Liverpool, Liverpool Reviews & Implementation Group, Liverpool, UK

  5. 5

    University Medical Center Freiburg, Pediatric Hematology & Oncology, Center for Pediatrics & Adolescent Medicine, Freiburg, Germany

  6. 6

    University Children's Hospital, Department of Neonatology, Tuebingen, Germany

*Joerg J Meerpohl, German Cochrane Centre, Medical Center - University of Freiburg, Berliner Allee 29, Freiburg, 79110, Germany. meerpohl@cochrane.de. joerg.meerpohl@uniklinik-freiburg.de.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 27 MAY 2014

SEARCH

 
Characteristics of included studies [ordered by study ID]
Vichinsky 2007

MethodsOpen label, randomised, parallel, multinational, multicentre trial


ParticipantsPeople with SCD:

Inclusion criteria

  • ≥ 2 years of age


  • iron overload from repeated blood transfusions


  • serum ferritin level for entry ≥ 1000 μg/l


  • receiving simple transfusions: LIC of ≥ 2 mg Fe/g dw


  • receiving exchange transfusions: LIC of ≥ 5 mg Fe/g dw


Exclusion criteria

  • serum creatinine above the ULN


  • significant proteinuria (as indicated by a urinary protein:creatinine ratio of ≥ 0.5 confirmed at two visits


  • active hepatitis B or C


  • second and third atrioventricular block, QT interval prolongation


  • therapy with digoxin or similar medications


  • chelation therapy-associated ocular toxicity


Further exclusion criteria as given in ClinicalTrials.gov

  • elevated liver enzymes in the year preceding enrolment
  • HIV seropositivity
  • history of nephrotic syndrome
  • uncontrolled systemic hypertension
  • fever and other signs/symptoms of infection within 10 days prior to the start of the study
  • diseases (cardiovascular, renal, hepatic, etc.) that would prevent the patient from undergoing any of the treatment options
  • psychiatric or addictive disorders that would prevent the patient from giving informed consent
  • history of drug or alcohol abuse within the 12 months prior to the study
  • pregnant or breast feeding patients
  • patients treated with systemic investigational drugs within 4 weeks or topical investigational drugs within 7 days before the start of the study
  • patients who require concomitant therapy with hydroxyurea
  • any surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any drug, such as gastrointestinal disease or major surgery, renal disease, difficulty voiding or urinary obstruction, or impaired pancreatic function


InterventionsDaily oral DFX (10 - 30 mg/kg according to baseline LIC; n = 132) versus subcutaneous DFO over 8 - 12 hours on 5 - 7 days/week (20 - 62 mg/kg according to baseline LIC; dose normalised to administration for 5 days/week; n = 63).


OutcomesSafety assessment

  • physical examination
  • laboratory testing: FBC, electrolytes, glucose, LFT, γ-GT, LDH, cholesterol, triglycerides, uric acid, total protein, CRP, copper and zinc levels
  • urinary testing: creatinine, total protein and albumin
  • ECG, audiometry, and ophthalmological tests


Efficacy assessment

  • liver iron concentration measured by SQUID
  • serum ferritin


Compliance was measured by number of tablets/vials returned


NotesThe sample-size calculation was based on the number of DFX-treated patients required to detect adverse effects with an underlying event rate of at least 4% with a 95% CI, according to the method of Hanley and Lippman-Hand (Hanley 1983).

ClinicalTrials.gov identifier: NCT00067080

Study ID number: CICL670A0109


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomised to receive deferasirox or deferoxamine in a 2:1 manner. The randomisation was performed using an interactive voice response system and was stratified according to the following age groups: 2 to < 6 years, 6 to < 12 years, 12 to < 16 years and 16 years and older. The randomisation sequence included permuted block groups of six patients for each of the three age strata."

Method of randomisation is not described, e.g. computer-generated random numbers.

Allocation concealment (selection bias)Low risk"The randomisation was performed using an interactive voice response system."

The included study did not report explicitly on concealment of allocation. However, since an interactive voice response system was used, we assumed that adequate allocation concealment was achieved.

Blinding (performance bias and detection bias)
All outcomes
High riskIt is classified as an open-label trial. There is no mentioning of blinding.

Incomplete outcome data (attrition bias)
All outcomes
High risk203 eligible patients were randomised, but only 195 received treatment and are included in the safety population. Reasons for this are not stated.

A similar percentage of patients of both groups (11.4% of the DFX group and 11.1% of the DFO group) either discontinued treatment due to adverse events (5.3% on DFX and 3.2% on DFO) or were lost to follow up (2 patients from the DFX group, 1 patient from the DFO group), withdrew consent (6 patients from the DFX group, 1 patient from the DFO group) or were excluded due to protocol violations (3 patients from the DFO group).

No intention-to-treat analysis with regard to efficacy was performed. Data are only presented as 'per protocol' although the actual numbers of patients analysed is not very clearly stated.

Selective reporting (reporting bias)High riskFerritin values were monitored monthly, clinical and laboratory assessment was performed for safety reasons also at 12, 24 and 36 weeks. LIC was also determined by SQUID at 24 weeks. These data are not reported.

Other biasUnclear riskA potential influence of the producer of deferasirox on the reporting of the results can not be excluded due to the cooperation between Novartis staff and the investigators.

Citation from Vichinsky 2007: "Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA) coordinated the design and execution of this trial and contributed to the analysis and interpretation of the trial data. Novartis Pharmaceuticals Corporation also collaborated with the external authors to assist in the development and approval of the manuscript for publication."

Vichinsky 2011

MethodsRandomized, open-label, active-control, safety/efficacy study.


ParticipantsInclusion criteria

  • age ≥ 2 years


  • male or female patients with SCD (SS, SC, SD, Sβo or Sβ+ thalassaemia)


  • iron overload from repeated blood transfusion, as defined below


    1. for patients > 16 years old receiving simple transfusions: lifetime history of receipt of at least 120 ml/kg or 30 adult units of packed red blood cells, or
    2. for patients ≤ 16 years old receiving simple transfusions: lifetime history of receipt of at least 120 ml/kg of packed red blood cells, or
    3. for all patients receiving exchange transfusions in the absence of a previous attempt to achieve negative iron balance: lifetime performance of at least 20 procedures, or
    4. for all patients: liver iron content ≥ 7 mg Fe/g


  • for entry into the screening period: serum ferritin of ≥ 1000 µg/mL on at least 2 occasions during the prior year obtained in the absence of concomitant infection


  • body weight > 10 kg


  • no known allergy or contraindication to the administration of DFO


  • ability to comply with all study-related procedures, medications, and evaluations


  • sexually active pre-menopausal female patients must use double-barrier contraception, oral contraceptive plus barrier contraceptive, or must have undergone clinically documented total hysterectomy or oophorectomy (or both), tubal ligation or be postmenopausal defined by amenorrhoea for at least 12 months.


  • written informed consent by the patient or for paediatric patient's consent of the patient's legal guardian


The definition of the term 'paediatric' for enrolment and study conduct will be in accordance with the local legislation.

Exclusion criteria

  • serum creatinine above the ULN


  • significant proteinuria


  • history of nephrotic syndrome


  • ALT ≥ 250 U/L at screening


  • clinical evidence of active hepatitis B or hepatitis C


  • history of HIV


  • fever or other signs/symptoms of infection within 10 days prior to the screening visit


  • uncontrolled systemic hypertension


  • history of MI, CHF or unstable cardiac disease not controlled by standard medical therapy


  • clinically relevant cataract or a previous history of clinically relevant ocular toxicity related to iron chelation


  • presence of a surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any study drug


  • history of drug or alcohol abuse within the 12 months prior to enrolment


  • pregnant or breastfeeding patients


  • patients treated with systemic investigational drug within 4 weeks prior or with topical investigational drug 7 days prior to the screening visit


  • randomisation in a previous clinical trial involving ICL670


Other protocol-related inclusion/exclusion criteria may apply.


InterventionsDFX (20 mg/kg; n = 135) once daily versus DFO subcutaneously 175 mg/kg/week (n = 68).

Dose adjustments were implemented for changes in patient weight, serum ferritin, serum creatinine, liver function tests and rash.


OutcomesPrimary outcome measures

  • to assess the safety of ICL670 compared to DFO during 24 weeks in patients with SCD and iron overload


Secondary outcome measures

  • to assess the long-term safety of ICL670 for up to 104 weeks in patients with SCD and iron overload


  • to assess the safety in ICL670 in a subgroup of the patients receiving concomitant hydroxyurea


  • to evaluate the efficacy of ICL670 versus DFO after 24 weeks in patients with SCD and iron overload


  • to evaluate the efficacy of ICL670 up to 104 weeks in patients with SCD and iron overload


NotesClinicalTrials.gov identifier: NCT00110617

Study ID number: CICL670A2201


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo information provided with regard to random sequence generation (neither in clinicaltrials.gov nor in ASH abstract). However, the allocation is characterized as "randomized".

Allocation concealment (selection bias)Unclear riskNo information provided with regard to allocation concealment (neither in clinicaltrials.gov nor in ASH abstract).

Blinding (performance bias and detection bias)
All outcomes
High riskIt is classified as an open-label trial. There is no mentioning of blinding.

Incomplete outcome data (attrition bias)
All outcomes
High risk9 participants from one site were excluded due to severe GCP violations.

For analysis, only patients who received study drug were considered (n = 191), i.e. 12 out of 68 are missing in the DFO group at 24 weeks. For efficacy analysis (ferritin) 18 patients in DFX and 6 patients in DFO were not considered.

Selective reporting (reporting bias)Low riskDetailed outcome data provided in clinicaltrials.gov.

Other biasUnclear riskA potential influence of the producer of DFX on the reporting of the results can not be excluded due to sponsoring by Novartis and cooperation between Novartis staff and the investigators.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Ware 2011SWiTCH trial: randomised non-inferiority trial comparing alternative treatment (hydroxyurea and phlebotomy) to standard treatment (transfusions and chelation) for reduction of secondary stroke and improved management of iron overload. This trial did not fulfil our stated inclusion criteria. Also, although chelation was mainly deferasirox based, deferoxamine was used in some patients.

 
Comparison 1. Deferasirox versus deferoxamine

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 2 Diabetes mellitus1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 3 Elevated ALT levels (> 5 UNL) on two consecutive visits2386Risk Ratio (M-H, Fixed, 95% CI)3.66 [0.47, 28.65]

 4 Abnormal liver function tests1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 5 Serum ferritin (µg/l)2283Mean Difference (IV, Fixed, 95% CI)440.69 [11.73, 869.64]

 6 LIC measured by SQUID Biomagnetometer (mg Fe/g dw); Overall population adjusted for transfusion category1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 7 LIC measured by SQUID Biomagnetometer (mg Fe/g dw); Per transfusion category subgroup1129Mean Difference (IV, Fixed, 95% CI)-1.29 [-2.85, 0.28]

    7.1 receiving simple transfusions
197Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.97, 1.57]

    7.2 receiving exchange transfusions
132Mean Difference (IV, Fixed, 95% CI)-5.20 [-8.56, -1.84]

 8 Creatinine increase2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Mild stable increases in serum creatinine
1195Risk Ratio (M-H, Fixed, 95% CI)1.64 [0.98, 2.74]

    8.2 Creatinine exceeding UNL
2386Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.12, 4.18]

 9 Change in creatinine from baseline (µmol/l)1195Mean Difference (IV, Fixed, 95% CI)3.24 [0.45, 6.03]

 10 Other adverse events (fixed-effect model)2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    10.1 Serious adverse events
2386Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.74, 1.27]

    10.2 Serious adverse events suspected to be related to study drug
1191Risk Ratio (M-H, Fixed, 95% CI)1.66 [0.19, 14.52]

    10.3 Any adverse event
1191Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.79, 0.98]

    10.4 Adverse events suspected to be related to study drug
1191Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.57, 1.54]

    10.5 Sickle cell anaemia with crisis
2386Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.82, 1.74]

    10.6 Headache
2386Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.58, 1.12]

    10.7 Abdominal pain
2386Risk Ratio (M-H, Fixed, 95% CI)1.52 [0.95, 2.46]

    10.8 Nausea
2386Risk Ratio (M-H, Fixed, 95% CI)2.06 [1.11, 3.80]

    10.9 Pyrexia
2386Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.66, 1.70]

    10.10 Vomiting
2386Risk Ratio (M-H, Fixed, 95% CI)1.16 [0.71, 1.88]

    10.11 Diarrhoea
2386Risk Ratio (M-H, Fixed, 95% CI)3.09 [1.53, 6.26]

    10.12 Back pain
2386Risk Ratio (M-H, Fixed, 95% CI)1.82 [0.87, 3.82]

    10.13 Upper respiratory tract infection
2386Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.45, 1.21]

    10.14 Arthralgia
2386Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.63, 2.48]

    10.15 Pain in extremity
2386Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.62, 2.32]

    10.16 Pharyngeal pain
2386Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.55, 2.10]

    10.17 Cough
2386Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.38, 1.08]

    10.18 Nasopharyngitis
2386Risk Ratio (M-H, Fixed, 95% CI)0.64 [0.35, 1.16]

    10.19 Nasal congestion
1191Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.18, 2.12]

    10.20 Rash
2386Risk Ratio (M-H, Fixed, 95% CI)2.39 [1.03, 5.55]

    10.21 Pruritus
1191Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.19, 1.75]

    10.22 Constipation
2386Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.50, 1.96]

    10.23 Chest pain
2386Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.34, 1.29]

    10.24 Viral infection
1195Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.14, 1.17]

    10.25 Urinary tract infection
1191Risk Ratio (M-H, Fixed, 95% CI)7.96 [0.47, 134.53]

    10.26 Insomnia
1191Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.09, 1.99]

    10.27 Dizziness
1191Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.05, 1.61]

    10.28 Injection site pain
1191Risk Ratio (M-H, Fixed, 95% CI)0.06 [0.00, 1.14]

    10.29 Cardio-respiratory arrest
1191Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.05, 30.41]

 11 Other adverse events (random-effects model)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 Back pain
2386Risk Ratio (M-H, Random, 95% CI)1.59 [0.47, 5.42]

    11.2 Constipation
2386Risk Ratio (M-H, Random, 95% CI)1.07 [0.34, 3.36]

    11.3 Abdominal pain
2386Risk Ratio (M-H, Random, 95% CI)1.49 [0.85, 2.61]

    11.4 Upper respiratory tract infection
2386Risk Ratio (M-H, Random, 95% CI)0.70 [0.35, 1.42]

    11.5 Pharyngeal pain
2386Risk Ratio (M-H, Random, 95% CI)1.00 [0.39, 2.53]

 12 Growth velocity (cm/year)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

    12.1 < 6 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.2 6 to < 12 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    12.3 12 - 16 years
1Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 13 Satisfaction1195Risk Ratio (M-H, Fixed, 95% CI)3.13 [1.99, 4.93]

    13.1 Patients previously on DFO
1121Risk Ratio (M-H, Fixed, 95% CI)3.56 [2.00, 6.35]

    13.2 Patients not on chelation therapy prior to study start
174Risk Ratio (M-H, Fixed, 95% CI)2.47 [1.18, 5.14]

 14 Convenience1195Risk Ratio (M-H, Fixed, 95% CI)3.85 [2.28, 6.47]

    14.1 Patients previously on DFO
1121Risk Ratio (M-H, Fixed, 95% CI)4.32 [2.19, 8.50]

    14.2 Patients not on chelation therapy prior to study start
174Risk Ratio (M-H, Fixed, 95% CI)3.16 [1.40, 7.13]

 15 Likelihood of continuing treatment1195Risk Ratio (M-H, Fixed, 95% CI)6.86 [3.38, 13.91]

    15.1 Patients previously on DFO
1121Risk Ratio (M-H, Fixed, 95% CI)8.01 [3.16, 20.34]

    15.2 Patients not on chelation therapy prior to study start
174Risk Ratio (M-H, Fixed, 95% CI)5.27 [1.79, 15.57]

 16 Discontinuations2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    16.1 Discontinuations due to AEs
2398Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.29, 3.63]

    16.2 Overall Discontinuations
2398Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.31, 0.92]

 
Summary of findings for the main comparison. Deferasirox versus deferoxamine for managing transfusional iron overload in people with sickle cell disease

Deferasirox versus deferoxamine for managing transfusional iron overload in people with sickle cell disease

Patient or population: patients with sickle cell disease and transfusional iron overload
Settings:
Intervention: deferasirox

Comparison: deferoxamine

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

DeferoxamineDeferasirox

Mortality
Follow up: 24 weeks
not estimable (event rate in study 0/56)not estimable (event rate in study 1/135)RR 1.26
(0.05 to 30.41)
191
(1 study)
⊕⊝⊝⊝
very low1,2

End-organ damage (incidence of diabetes)
Follow up: 24 weeks
not estimable (event rate in study 0/56)not estimable (event rate in study 1/135)RR 1.26
(0.05 to 30.41)
191
(1 study)
⊕⊝⊝⊝
very low1,3

LIC measured by SQUID biomagnetometer (mg Fe/g dw); overall population adjusted for transfusion category
Follow up: 52 weeks
The mean LIC measured by SQUID biomagnetometer (mg Fe/g dw) in the intervention group was 0.2 lower (3.15 lower to 2.75 higher)173
(1 study)
⊕⊕⊕⊝
moderate1

Serum ferritin (µg/l)
Follow up: 24 to 52 weeks
The mean serum ferritin (µg/l) in the intervention groups was
440.69 higher
(11.73 to 869.64 higher)
283
(2 studies)
⊕⊕⊕⊝
moderate1

AE: Change in creatinine from baseline (µmol/l)
Follow up: 52 weeks
The mean creatinine change from baseline in the intervention group was 3.24 higher (0.45 to 6.03 higher)195
(1 study)
⊕⊕⊕⊝
moderate1

Discontinuations
Follow up: 24 to 52 weeks
168 per 100089 per 1000
(52 to 155)
RR 0.53
(0.31 to 0.92)
398
(2 studies)
⊕⊕⊝⊝
low1,4

Satisfaction
Follow up: 12 months
238 per 1000745 per 1000
(474 to 1000)
RR 3.13
(1.99 to 4.93)
195
(1 study)
⊕⊕⊕⊝
moderate1

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

AE: adverse events; CI: confidence interval; dw: dry weight; Fe: iron; LIC: liver iron concentration; RR: risk ratio; SQUID: superconducting quantum interference device

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

 1 No ITT analysis with regard to efficacy. Unclear risk of other bias due to involvement of sponsor and possibility of selective reporting. See also risk of bias table.
2 Mortality due to iron overload cannot be adequately assessed in studies with a maximum follow up of 52 weeks.
3 Wide 95% confidence interval.
4 Serious inconsistency with an I² of 77%.
 
Table 1. Characteristics of included patients (Vichinsky 2007)

Deferasirox

(n = 132)
Deferoxamine

(n = 63)
All patients

(n = 195)

Age, years

Median151615

Range3 - 543 - 513 - 54

Age group, # of patients (%)

< 6 years4 (3.0)3 (4.8)7 (3.6)

6 to < 12 years30 (22.7)15 (23.8)45 (23.1)

12 to < 16 years33 (25.0)13 (20.6)46 (23.6)

16 to < 50 years63 (47.7)31 (49.2)94 (48.2)

50 to < 65 years2 (1.5)1 (1.6)3 (1.5)

Sex, # of patients (%)

Female80 (60.6)35 (55.6)115 (59.0)

Male52 (39.4)28 (44.4)80 (41.0)

Race, # of patients (%)

Caucasian8 (6.1)3 (4.8)11 (5.6)

Black118 (89.4)59 (93.7)177 (90.8)

Others6 (4.5)1 (1.6)7 (3.6)

Ferritin, μg/l

Median3'4602'8343'298

Range1'082 - 12'9011'015 - 15'5781'015 - 15'578

Baseline ALT, # of patients (%)

≤ 2.5 ULN110 (83.3)58 (92.1)168 (86.2)

> 2.5 ULN21 (15.9)5 (7.9)26 (13.3)

Missing1 (0.8)-1 (0.5)

History of HAV and/or HBV, # of patients (%)

Present10 (7.6)4 (6.3)14 (7.2)

Absent122 (92.4)59 (93.7)181 (92.8)

Prior chelation therapy, # of patients (%)

Deferoxamine or deferiprone83 (62.9)38 (60.3)121 (62.1)

No prior chelation therapy49 (37.1)25 (39.7)74 (37.9)

Blood transfusions during study (units of packed RBCs)

Median121212

Range0 - 241 - 220 - 24

 ALT: alanine aminotransferase
HAV: hepatitis A virus
HBV: hepatitis B virus
RBCs: red blood cells
ULN: upper limit of normal
 
Table 2. Dosing algorithm according to LIC groups and average daily doses administered (Vichinsky 2007)

Baseline LIC (mg Fe / g dw)


Baseline LIC group≤ 3> 3 - ≤ 7> 7 - ≤ 14> 14

Deferasirox (n = 132)(n = 4)(n = 64)(n = 46)(n = 18)

Protocol assigned dose5 mg/kg10 mg/kg20 mg/kg30 mg/kg

Reported mean LIC ± SD2.5 ± 0.47.9 ± 5.59.8 ± 1.917.5 ± 3.0

Adjusted mean LIC ± SD5.0 ± 0.815.8 ± 11.019.6 ± 3.835.0 ± 6.0

Deferasirox dose (mg/kg)9.5 ± 3.213.0 ± 3.119.7 ± 2.128.0 ± 2.8

Min - Max deferasirox dose5.0 - 12.38.4 - 23.910.0 - 24.522.8 - 30.0

Deferoxamine (n = 63)(n = 6)(n = 21)(n = 20)(n = 16)

Protocol assigned dose20 - 30 mg/kg25 - 35 mg/kg35 - 50 mg/kg≥ 50 mg/kg

Reported mean LIC ± SD3.9 ± 3.55.2 ± 2.18.6 ± 3.014.3 ± 5.4

Adjusted mean LIC ± SD7.8 ± 7.010.4 ± 4.217.2 ± 6.028.6 ± 10.8

Deferoxamine dose (mg/kg)22.9 ± 3.928.7 ± 3.236.6 ± 9.550.0 ± 7.3

Min - Max deferoxamine dose20.0 - 29.521.6 - 34.47.0 - 52.632.4 - 62.0

Deferasirox / Deferoxamine dose ratio1 : 2.41 : 2.21 : 1.851 : 1.8

 dw: dry weight
FE: iron
LIC: liver iron concentration
SD: standard deviation
 
Table 3. Characteristics of included patients (Vichinsky 2011)

Deferasirox (n = 135)Deferoxamine (n = 68)All Patients (n = 203)

Age, years

Mean ± Standard deviation16.4 ± 10.3116.2 ± 10.1516.3 ± 10.23

Age group, # patients (%)

2 to < 6 years6 (4.4)4 (5.9)10 (4.9)

6 to < 12 years42 (31.1)21 (30.9)63 (31.0)

12 to < 16 years35 (25.9)18 (26.5)53 (26.1)

16 to < 50 years50 (37.0)24 (35.3)74 (36.5)

50 to < 65 years2 (1.5)1 (1.5)3 (1.5)

= 65 years000

Gender, # patients (%)

Female56 (41.5)33 (48.5)89 (43.8)

Male79 (58.5)35 (51.5)114 (56.2)

Race, # patients (5)

Caucasian2 (1.5)02 (1.0)

Black130 (96.3)65 (95.6)195 (96.1)

Oriental000

Other3 (2.2)3 (4.4)6 (3.0)

Weight group, # patients (%)

< 15 kg000

15 to < 35 kg39 (28.9)23 (33.8)62 (30.5)

35 to < 55 kg43 (31.9)18 (26.5)61 (30.0)

55 to < 75 kg42 (31.1)22 (32.4)64 (31.5)

=75 kg10 (7.4)3 (4.4)13 (6.4)

Missing1 (0.7)2 (2.9)3 (1.5)

History of splenectomy, #patients (%)

Yes22 (16.3)10 (14.7)32 (15.8)

No113 (83.7)58 (85.3)171 (84.2 )

Serum ferritin, ng/mL

Median34063300n.a.

Range920 - 125351178 - 16535n.a.

Serum ferritin category, # of patients (%)

≤ 1000 ng/mL4 (3.0)04 (2.0)

> 1000 - ≤ 2500 ng/mL34 (25.2)28 (41.2)62 (30.5)

> 2500 - ≤ 4000 ng/mL45 (33.3)16 (23.5)61 (30.0)

> 4000 ng/mL52 (38.5)24 (35.3)76 (37.4)

Transfusional iron intake, mL RBC/kg/day

Median0.30.3n.a.

Range0.1 - 2.4-0.1 - 0.8n.a.

Dose of iron chelating drug, mean (SD)

Planned dose (mg/kg/day)19.8 (2.0)41.1 (4.6) *n.a.

Received dose (mg/kg/day)19.6 (2.2)34.1 (4.7) *n.a.

 * based on dose per day over 5 days/week
RBC: red blood cells