Deferasirox Treatment In Patients Research Articles

Early Kidney Damage Markers after Deferasirox Treatment in Patients with Thalassemia Major: A Case-Control Study.

Background The life of patients with β-thalassemia major depends on blood transfusion. Regular blood transfusion leads to hemosiderosis in their main organs. The aim of this study was to compare the effects of deferasirox and deferoxamine on renal damage in patients with β-thalassemia major. Method The present case-control study was conducted on 60 individuals who were referred to the 17th Shahrivar Tertiary Referral Hospital in Guilan province, Iran. In this study, patients with β-thalassemia major who used deferasirox (n = 21) and patients who used deferoxamine (n = 19) were evaluated. The control group (n = 20) was selected from healthy individuals. Serum creatinine (CREA), blood urea nitrogen (BUN), and Cystatin C were measured from blood samples. Furthermore, urinary (U.) neutrophil gelatinase-associated lipocalin (NGAL), albumin (Alb), interleukin- (IL-) 18, and Kidney Injury Molecule-1 (KIM-1) were measured by the ELISA method and normalized for U. creatinine (CREA). Results U. NGAL, U. IL-18, and BUN biomarkers in the deferasirox group were significantly higher than those in the control group (p < 0.001). U. NGAL/CREA and U. KIM-1/CREA ratios increased in both the deferoxamine and deferasirox groups compared to the control group (p < 0.05). U. Alb was significantly higher in patients treated with deferoxamine than in healthy participants (p < 0.05). Conclusion The findings of this study indicate that after taking deferasirox, there was renal damage and an increase in inflammatory factors. Also, minor renal impairment was observed after deferoxamine administration, but it was not confirmed at the molecular level (U. NGAL and KIM-1). Therefore, it seems that patients who are taking these two drugs should be monitored carefully.

Bone Marrow Iron Assessment By MRI-R2* and Its Relation to Deferasirox Treatment in Patients with Iron Overload

Objective: Patients with iron overload suffer from different organ damage due to increased iron concentration. Iron overload in the bone marrow and the influence of iron chelation therapy on bone marrow iron content may play an additional role in these patients and is until now not well examined.Material and Methods: We performed MRI-R2* measurements in the vertebral bone marrow using water-fat chemical shift relaxometry for estimation of iron and fat content in comparison to hepatic and splenic iron concentrations and serum ferritin in patients with iron overload due to hereditary hemochromatosis (HHC) and patients with siderosis due to red blood cell transfusions and /or iron loading anemia.112 patients with iron overload, mean age: 32 y (transfusion dependent thalassemia major (TM) n=65, Diamond-Blackfan anemia (DBA) n=12, HHC n=10, iron loading anemia (EA) n=7, transfusion siderosis n=12 and stem cell transplantation n=6) and 14 control subjects underwent MRI for determination of the transverse relaxation rate R2*assessed from ROI based signal intensities of one transversal slice (10mm) through the liver, spleen, and mid-vertebral bone marrow.Breathhold water-fat relaxometry (12 echo times, TE=1.3-26ms, FA=20°, bandwidth=1955Hz/px) was performed to determine apparent fat contents (aFC) and bone marrow R2*. Additionally, serum ferritin values were assessed.In 67 patients with TM under chelation therapy with Deferasirox (DFX) we compared R2* bone marrow iron content with the ratio of the chelator dose rate (Deferasirox, [mmol/d]) to the total liver iron (LivFe = LIC*volume [g-Fe]).Results: Relative to controls (n=14, R2* = 95s-1) and HHC (n=10, R2* = 95s-1), median bone marrow R2* rates were significantly increased in patients with TM (n=65, R2* = 398s-1, p<10-4) or DBA (n=12, R2* = 252s-1, p = 0.005). R2* of the bone marrow significantly correlated with serum ferritin (rS=0.52, p<10-4), splenic R2* (rS=0.43, p<10-4), cardiac R2* (rS=0.43, p<10-4), and hepatic R2* (rS=0.37, p<10-4). No significant correlation of aFC with marrow R2* could be obtained.The bone marrow iron content was higher in patients with a low Deferasirox (DFX) dose. A DFX dose > 150 (mmol/d)/g-Fe was a negativ predictor for increased bone marrow iron content (R2* > 700 1/s), but a significant correlation couldn't be found (r = 0,077), probably due to the low number of patients. The efficacy dose of DFX for a low bone marrow iron content seems to lay between a dose of 1mmol/d (18mg/d) and 2,5 mmol/d (45mg/d). A DFX dose > 2,5 mmol/d didn't seem to increase the efficacy.Table 1Diagnosis (n)Age Median (IQR)KM R2* [s-1 ] Median (IQR)KM R2* 95 % rangeControl group (14)29.8 (26.0)95 (43)62 - 134TM ( 65)30.6 (16.2)398 (455)73 - 1213HH (10)56.4 (9.3)95 (40)61 - 270EA (7)46.6 (24.8)191 (93)159 - 490DBA (12)27,6 (14.6)252 (250)62 - 652TS(12)32.3 (46.2)322 (304)116 - 607BMT (6)20 (20.8)285 (342)105 - 470Conclusion: Water-fat chemical shift relaxometry allows precise determination of bone marrow R2* rates and estimation of the apparent fat content, which may add additional information to these patients. Patients with transfusion related iron overload have significant higher bone marrow iron content than patients with iron overload due to hereditary hemochromatosis. DFX in an adäquat dose seem to prefent bone marrow iron overload. DisclosuresGrosse:Swedish Orphan Biovitrum: Honoraria; Novartis Oncology: Honoraria, Research Funding.

Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia-negative myeloproliferative neoplasms in fibrotic phase (FP-MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP-MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8months (IR 7.1-43.1) with median ferritin values of 1415ng/mL (IR 1168-1768). Extra-hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6months of treatment), after a median treatment period of 15.4months (IR 8.1-22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3months) rise of Hb levels >1.5g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP-MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.

Hematological Improvement during Deferasirox Treatment in Patients with Myeloproliferative Neoplasms (MPN)

Background Deferasirox (DFX) is an oral iron chelator widely employed to reduce iron overload in patients with myelodysplastic syndromes; in this subset, an unexpected hematological improvement (HI) has been reported in about 20% of cases by several groups. At present, only few case reports showed a similar HI in patients with Ph- Myeloproliferative Neoplasms (MPN) and transfusional requirement receiving DFX treatment.Aim To address the incidence of HI during DFX treatment in MPN patients, we revised all patients with MPN and iron overload secondary to transfusional requirement enrolled in the database of our regional cooperative group who received a treatment with deferasirox.Methods Twenty-eight patients [M/F 22/6, median age at diagnosis 68.8 years, interquartile range (IQR) 63.2 – 74.3] were reported in the database. Of them, 25 had a primary Myelofibrosis, 2 a post Essential Thrombocythemia myelofibrotic phase (MP) and 1 a post Polycythemia Vera MP. An HI was considered as a rise in Hb values ≥ 1.5 g/dl and/or a reduction in the transfusional requirement ≥ 50% lasting at least 3 months.Results Treatment with DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1 – 43.1) and from transfusion requirement of 10.0 months (IR 5.7 – 15.9). Median Hb and ferritin values at baseline were 7.8 g/dl (IQR 7.2 – 8.4) and 1,415 ng/ml (IQR 1,168 – 1768), respectively. Starting DFX dose was 1,500 mg/day in 13 patients, 1,250 mg/day in 5 patients, 1,000 mg/day in 9 patients and <1,000 mg/day in 1 patient. Extra-hematological toxicity was reported in 16/28 patients (57.1%) and a dose reduction/temporary discontinuation was needed in 12 cases (42.8%), but only 2 patient went off treatment due to toxicity. Twenty-six patients were considered evaluable for response (≥ 6 months of treatment): after a median treatment period of 15.4 months (IR 8.1 – 22.3), 11 patients (42.3%) achieved a reduction of iron overload with ferritin levels < 1,000 ng/ml. As to HI, 6/26 patients (23.0%) showed an unexpected and persistent (> 3 months) rise of Hb levels > 1.5 g/dl, with disappearance of transfusional requirement in 4 cases and reduction ≥ 50% in the remaining 2 cases. The main clinical features of these 6 patients at DFX initiation and at HI are reported in the Table. Table 1GenderAge (yrs)Months from diagnosisMonths from transfusionsHb (g/dl)Ferritin (ng/ml)Hb at HI (g/dl)Ferritin at HI (ng/ml)Months to HI# 1M68.7101.545.28.21,59010.127218# 2M67.513.313.28.7130911.265912# 3M77.29.86.08.017909.6168212# 4F76.721.715.39.1121410.5104112# 5M71.86.94.66.8264110.884924# 6M67.179.46.78.070610.05006The HI was achieved together with a reduction of ferritin levels in 4 cases, while it was independent by ferritin response in the remaining 2 cases. To identify factors predicting the achievement of HI, many features at baseline (age, gender, Hb and ferritin levels, interval from diagnosis to DFX treatment) were compared between patients obtaining or not HI: however, none of them showed a significant role.Conclusions Treatment with DFX is feasible and effective in MPN with iron overload. Moreover, it is worth of note and deserves further biological and clinical insights that also in this setting an hematological improvement can occur in a sizeable rate of patients. DisclosuresLatagliata:Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy. Breccia:Celgene: Consultancy; BMS: Consultancy; novartis: Consultancy.

Deferasirox Therapy in Children With Fanconi Aplastic Anemia

Thirty-nine children with Fanconi aplastic anemia (FAA) have been followed up in our center between January 2008 and November 2010. Eight of these children (20%) with a transfusional iron overload had been undergoing deferasirox treatment during the study period. In the English literature, transfusional iron overload and the use of an iron chelator in children with FAA has not yet been evaluated. Here, we have presented the effectivity and tolerability of deferasirox in children with FAA and a transfusional iron overload. Before the deferasirox treatment, the mean serum ferritin level was 3377 ± 2200 ng/mL. After a mean 13.6-month treatment duration, the mean ferritin level decreased to 2274 ± 1300 ng/mL (P<0.05). In our series, 3 patients had renal and 3 had hepatic toxicity during the treatment. Two patients had peliosis hepatis and 2 had congenital renal abnormalities before the treatment. There may be differences in the side-effect profiles of deferasirox treatment in patients with FAA. In our series, despite the low number of cases, nephrotoxicity and hepatotoxicity were common side effects instead of gastrointestinal disturbances reported in other studies. Deferasirox is an oral, easily applicable, and effective iron chelator; baseline hepatotoxicity and nephrotoxicity may increase the development of toxic side effects in children with FAA. Patients with FAA receiving deferasirox treatment should be followed up closely for these side effects.

Iron chelation therapy for patients with sickle cell disease and iron overload

A 21-year-old male with sickle cell disease (SCD) presented with severe pallor. He had received a total of 100 red blood cell (RBC) units in his lifetime, had a mean serum ferritin level of 3133 ng/ml, and liver iron concentration (LIC) of 12 mg Fe/g dry weight (dw). He was started on subcutaneous deferoxamine (DFO) infusions at a dose of 56 mg/kg/d, five days a week (equivalent to 40 mg/kg/d, seven days a week) and continued to receive 8–10 RBC units/year as treatment for pain. During the first six months of chelation therapy, his serum ferritin levels fell by around 50% of the pretreatment value, but then started to increase back up to the baseline values. The patient was noncompliant with DFO therapy. He experienced pain at the site of injection, could not sleep and was concerned about carrying a pump and not being accepted by his peers. He dropped out of college and abstained from all social activities. He was referred to a psychologist; however, this failed to improve compliance and he opted to stop DFO therapy altogether.

Evaluation of Deferasirox (Exjade®, ICL670) Therapy in Patients with Transfusional Iron Overload Who Achieve Serum Ferritin (SF) ≤1000 ng/mL in Long-Term Studies.

Background: Maintaining SF levels below 1000 ng/mL offers significant clinical benefits in patients with transfusional iron overload. However, low SF levels can be associated with an increased risk for iron chelator toxicity. This analysis was performed to assess safety parameters during deferasirox treatment in patients with transfusion-dependent anemias who reached SF levels ≤1000 ng/mL on at least two consecutive visits during the extension phases of four core studies.Methods: Patients (≥2 years old) with β-thalassemia, MDS, sickle cell disease or other transfusion-dependent anemias enrolled in four clinical trials were treated for 1 year with deferasirox 5–30 mg/kg/d, followed by extension phases of 4 years. In the extension phases, patients either continued receiving deferasirox (deferasirox cohort) or crossed over from DFO to deferasirox (crossover cohort), while receiving dose modifications based on efficacy and safety parameters. Efficacy was monitored by monthly SF readings; safety was assessed by the incidence and type of adverse events (AEs).Results: Following dose adjustments at the end of the core trials, 163/652 (25%) patients in the deferasirox cohort reached SF levels ≤1000 ng/mL on at least two consecutive visits after a median of 1.2 years on deferasirox therapy. Median SF levels over the course of the studies are presented in Table. At month 22, the overall mean dose was 20 mg/kg/d, which was generally maintained in all dose groups until month 42. At baseline, overall mean (±SD) ALT and AST values were 44.2 (36.2) and 39.2 (27.4) U/L, respectively. Overall ALT and AST levels decreased by 16.5 (±38.7) and 11.7 (±30.5) U/L, respectively, at month 42.Median SF (ng/mL)Initial dose groupMonth5 and 10 mg/kg/d20 mg/kg/d30 mg/kg/d(n)(n)(n)Baseline1295 (55)1520 (43)2311 (65)11475 (54)1616 (42)2284 (65)61612 (54)1383 (39)1596 (60)12*1697 (53)1165 (42)1168 (62)181818 (45)1362 (39)1307 (51)241287 (49)1161 (34)1236 (52)30966 (44)1046 (33)1047 (54)36788 (37)1010 (30)991 (50)42884 (37)1040 (34)850 (50)*Dose modifications to most appropriate dose10 (6.1%) patients experienced two consecutive serum creatinine increases >33% above baseline and >ULN. Most of these increases were only marginally >ULN and none were >2 x ULN. Creatinine increases were non-progressive and generally fell promptly following dose reductions of 5–10 mg/kg/d. No new AEs or safety concerns have been reported thus far in this population.Conclusions: With appropriate deferasirox dosing, iron overloaded patients can effectively achieve and maintain low SF levels. There were no major safety issues observed in achieving SF levels of ≤1000 ng/mL in this population. Decreases in liver enzymes suggest improvement in liver function, probably as a result of reduced iron burden.