No abstract

Patients with thalassemia major requiring regular blood transfusions accumulate iron that is toxic to the heart, liver, and endocrine systems. The following prospective, randomized trial was carried out to determine the effectiveness, in children and young adults, of combined deferiprone (DFP) and deferoxamine (DFO) in reducing transfusional iron overload compared to either drug alone and to assess the safety and tolerability of DFP. Sixty-six patients were randomized into three treatment arms: daily DFP combined with DFO twice weekly; daily DFP only; and DFO only 5 days/week. Fifty-six patients completed the 54 weeks and were assessed by different indices. A significant reduction of liver iron concentration and serum ferritin was observed in all three arms while significant reduction of liver iron score was observed in patients on combination therapy only. Cardiac function did not significantly change in any arm. Compliance improved in patients who received combined therapy. Toxicity of DFP was mild to moderate and acceptable; most commonly, transient arthropathy and nausea/vomiting were observed. Thus, combination therapy has shown to be effective in reducing iron overload in thalassemia patients.

No abstract

Forodesine and nelarabine (the pro-drug of ara-G) are 2 nucleoside analogues with promising anti-leukemic activity. To better understand which pediatric patients might benefit from forodesine or nelarabine (ara-G) therapy, we investigated the in vitro sensitivity to these drugs in 96 diagnostic pediatric leukemia patient samples and the mRNA expression levels of different enzymes involved in nucleoside metabolism. Forodesine and ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)-ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms. Differences in sensitivity could be partly explained by significantly higher accumulation of intracellular dGTP in forodesine-sensitive samples compared with resistant samples, and higher mRNA levels of dGK but not dCK. The mRNA levels of the transporters ENT1 and ENT2 were higher in ara-Gsensitive than -resistant samples. We conclude that especially T-ALL, but also BCP-ALL, pediatric patients may benefit from forodesine or nelarabine (ara- G IntroductionLeukemia is the most common childhood malignancy, and the general incidence in both adults and children of acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) is approximately 1 per 100 000 and 2-3 per 100 000, respectively. Although overall cure rates have been improved over the last decades, approximately 20% of children with ALL and 40% of children with AML still eventually die from their disease. 1,2 In adults, the prognosis is worse with a survival below 60% in ALL 3 and 50% in AML, 4 indicating that there is still a great need for better therapy. Currently, purine nucleosides analogues are in clinical trials for different types of leukemia including clofarabine, forodesine (BCX-1777/Immucillin H), and nelarabine (506U78/Arranon/ Atriance) the latter being the pro-drug for 9-␤-D-arabinofuranosylguanine (ara-G).Forodesine is a noncleavable inosine analog developed to bind and inhibit the purine nucleoside phosphorylase (PNP) enzyme. 5 PNP normally degrades excess of intracellular deoxyguanosine (dGuo) into guanosine and deoxyribose-1-phosphate through phosphorylysis. dGuo is continuously produced in the body as the result of DNA degradation during cellular turnover. Inhibition of PNP by forodesine results in the intracellular accumulation of dGuo. DGuo is rapidly phosphorylated to dGTP in the purine salvage pathway leading to dGTP accumulation. 6,7 High intracellular levels of dGTP cause cell death through mechanisms that are still not fully understood, but which may likely involve imbalance in the deoxynucleotide pool and/or inhibition of ribonucleotide reductase 8 resulting in inhibition of DNA synthesis and/or by activation of a p53-induced cell-cycle arrest and apoptosis. 9 Whereas most nucleoside analogues depend on DNA incorporation to exert their toxic effect, this is not the case for forodesine. T cells seem...

Several clinical studies have shown that the combination of deferiprone (DFP) with desferrioxamine (DFO) is efficacious with regard to decrease in serum ferritin (SF), reduction of liver iron concentration (LIC) and increase in urinary iron excretion (UIE) in patients (pts) suffering from thalassemia major (TM). However, there is lack of randomized controlled trials comparing the efficiacy and safety of the combination therapy versus DFP or DFO monotherapy. This is the first randomized controlled trial analyzing and comparing changes of LIC and total iron excretion (TIE) in pts treated with the combination therapy versus pts treated with DFP or DFO monotherapy during a study period of one year. A total of 95 pts with TM were randomized into one of the following three treatment arms: DFP was given orally at a daily dose of 75 mg/kg either alone, in combination with s.c. DFO (40–50 mg/kg twice weekly) or DFO was given alone at a dose of 40–50 mg/kg 5 days a week (control arm). All pts had been treated with DFO prior to the study. LIC was measured in biopsies at baseline and after one year. TIE / day was calculated as (iron transfused during study period (mg) + (LIC at T0 - LIC at T1y) x 10.6 x body weight in kg) / number of days on treatment between biopsies. Biochemistry measurements including SF and liver enzymes were performed at 3-monthly intervals. Blood counts were analyzed weekly for 8 weeks and thereafter bi-weekly. Cardiac function (ECHO) was assessed 6-monthly. UIE was measured quarterly; in pts receiving combination therapy on two different days, i.e. during DFP and combination therapy. Compliance was excellent in all three treatment arms. In total, 14 pts (15%) dropped out from the study: one due to biopsy failure at baseline, five withdrawals from informed consent, four non-compliance to treatment, one due to jaundice, one died from arrhythmia induced heart failure, and two (2.1%) developed agranulocytosis. The most common adverse events were transient increase in liver enzymes, nausea and arthralgia. The average change in LIC after one year was most pronounced in the combination arm (−47%; p=0.001), but LIC was also significantly lowered after one year monotherapy with DFO (−23%; p=0.13) or DFO (−45%; p=0.003). A reduction of the liver iron score acc. to Sciot was observed in all three treatment arms and the change after one year compared to baseline was statistically significant in the combination arm (p=0.0013). Further, the combination regimen was associated with the highest TIE (mean±SD: 0.46±0.22 mg/kg/d; p=0.00003). The majority of pts in all treatment arms showed a clear decrease in SF and the mean SF was significantly reduced in the combination arm after one year (−2′120μg/L; p=0.0003). The left ventricular ejection fraction increased during combination therapy (+3.4% absolute units; p=0.19), whereas it slightly decreased (−2.1% absolute units; p=0.41 and p=0.55, respectively) after either DFP or DFO treatment. The mean daily UIE was higher in DFP-containing regimens than with DFO single agent therapy. UIE on days of combination (0.90±0.33 mg/kg/24h) was significantly higher than on days of DFP monotherapy (0.53±0.26 mg/kg/24h) (p=0.0003). This study indicates that the combination of daily DFP and twice weekly DFO at standard doses is a highly efficacious and safe chelation therapy for pts with TM.