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Introduction: The safety and tolerability profile of the oral iron chelator deferasirox has been established in five comprehensive trials (with a 1-year core phase) in adults and children with a range of transfusion-dependent anemias. Following completion of the core phase, pts entered an extension phase that will last for 4 years. This analysis presents cumulative long-term safety data during deferasirox treatment. Methods: Safety was assessed monthly, primarily by evaluating the incidence and type of adverse events (AEs) and measuring laboratory parameters. Results: A total of 1033 pts have received deferasirox: 703 initially received it during the core phases (deferasirox cohort) and 330, who initially received deferoxamine (DFO), crossed over to deferasirox in the extension phases (crossover cohort); 433 (41.9%) were pediatric pts aged 2-4% overall) drug-related AEs during deferasirox treatment (median 1.5–2.5 years; n=1033) During the extension phases there were no changes in markers of liver or renal function that were consistently or significantly different from the core study. Ten pts (1.0%) had urinary total protein/creatinine ratio >1.0 at 2 consecutive visits. There have been no cases of progressive increases in serum creatinine, indicative of renal insufficiency or failure. Physical and sexual development proceeded normally in all pediatric pts. Conclusions: The safety and tolerability of deferasirox in pts receiving up to 2.5 years of treatment was similar to that observed during the 1-year core trials, with most AEs being mild, transient and easily manageable. These data demonstrate that long-term treatment with deferasirox is generally well tolerated in adults and children with a variety of transfusion-dependent anemias.

^Renal Safety Board (RSB) member Introduction: Deferasirox has been evaluated in a series of 1-year clinical trials in patients with a variety of transfusion-dependent anemias. Mild, non-progressive increases (ie initial rises, then stabilization) in serum creatinine >33% above baseline were observed in approximately one-third of patients receiving deferasirox. Following completion of the core trials, patients have entered 4-year extension phases to evaluate the long-term safety and efficacy of deferasirox. This is an analysis of renal function in patients receiving deferasirox in two ongoing extension phases. Methods: Initial deferasirox dose was assigned by baseline iron burden in the core trials, and tailored to meet individual patient needs in the extension phases. Serum creatinine and urinary protein/creatinine ratios were measured monthly. Creatinine increases >33% above baseline on ≥2 consecutive values, ≥7 days apart, were selected by the RSB for dose review. Results: Of the 480 patients who initially received deferasirox, 387 entered the extension phases and 334 were on treatment at the time of analysis; the median duration of treatment was 2.5 years. In patients who started on deferasirox 20 and 30 mg/kg/day, non-progressive, dose- and iron intake-dependent creatinine increases were noted by week 4 (Figure). In patients who initially received deferasirox 5 and 10 mg/kg/day, a small, non-progressive increase also occurred near week 52, coinciding with dose escalation to 20 or 30 mg/kg/day. These patterns were consistent irrespective of age or underlying anemia. Similar trends were observed with creatinine clearance. Of the 480 patients, creatinine levels increased marginally above the upper limit of normal (ULN) at some point during the 2.5-year observation period in 12.1%. With or without dose reduction, most (72.4%) returned ULN. No follow-up information was available in 7.1% of patients at the time of data cut-off. Median creatinine values up to 2.5 years (lines indicate 25-75th percentiles) Median creatinine values up to 2.5 years (lines indicate 25-75th percentiles) These non-progressive creatinine increases were generally reversible with dose modification/interruption. In 36 episodes of treatment interruption, preceded by creatinine increases >33% above baseline, overall median creatinine levels decreased from 77.8 to 62.8 μmol/L. Levels fell below the 33% above baseline in the remaining 11, where treatment was either resumed early or the patient was off-treatment at the time of analysis. Ten patients (1.0%) had urinary total protein/creatinine ratio >1.0 at two consecutive visits. Conclusions: This 2.5-year analysis of renal function in patients receiving deferasirox confirms that early changes in creatinine/creatinine clearance observed in 1-year core trials are non-progressive with continued treatment. The small changes in creatinine/creatinine clearance noted when patients were dose-escalated from 5/10 mg/kg/day at the end of the core trials, were also non-progressive. These changes were manageable with appropriate dose modification.

Transfusional hemosiderosis is often associated with hepatic siderosis or infection with hepatotropic viruses, resulting in hepatocellular injury and progression to chronic liver disease. Liver biopsy is the method of choice for directly assessing damage; scales have been developed to measure necroinflammatory activity (grading) and tissue fibrosis (staging). Iron chelation therapy is historically known to decrease morbidity associated with hepatosiderosis. Aim: To assess 1 year’s chelation therapy with the novel once-daily oral chelator, deferasirox (DSX), or the current standard deferoxamine (DFO), on pathology of liver tissue in chronically transfused patients. Methods: Liver biopsy was performed at baseline and after 1 year in patients participating in DSX Studies 0107 (n=454) and 0108 (n=101). All patients, except 25 in 0107 and 3 in 0108, had liver tissue evaluated by pathology. In 0107, patients with β-thalassemia were randomized to DSX (5, 10, 20 or 30 mg/kg/day; n=224) or DFO ( Results: DSX and DFO dose-dependently affected grading, which mirrored effects on LIC and serum ferritin. DSX 5 and 10 mg/kg increased these parameters, while stabilization and decreases were seen with the highest doses of both chelators, regardless of hepatitis C status. In 0107, a decrease in mean ±SD necroinflammatory score was noted with DSX 30 mg/kg (2.5 ±1.6 to 1.7 ±1.3, n=95) and DFO ≥ 50 mg/kg 5 days/week (2.1 ±1.6 to 1.4 ±1.3, n=95). Similar results were observed in 0108 for β-thalassemia (2.4 ±1.7 to 1.7 ±1.6, n=58) and rare anemia patients (1.8 ±1.5 to 1.5 ±1.3, n=40). This decrease was accompanied by dose-dependent modification of available liver enzyme levels in 0107 (Table); with a similar trend in 0108. No obvious modification of staging was observed after 1 year of treatment, suggesting that longer time periods are needed to observe potential reversal of fibrosis. Change in liver enzymes (ALT; U/L) by treatment (Study 0107) DSX, mg/kg DFO, mg/kg 5 10 20 30 Conclusions: Although the data show considerable variability, results suggest that chelation therapy with DSX or DFO is associated with reduced hepatocellular inflammation and improved liver function. These modifications appear to be linked with effects on LIC and serum ferritin levels.

Chelation therapy is the conventional treatment for transfusional iron overload, which leads to complications in the heart, liver and endocrine glands. A 1-year, open-label, multicenter, Phase III study compared the investigational, once-daily, oral iron chelator deferasirox (DSX) with deferoxamine (DFO) in adult and pediatric β-thalassemia patients aged ≥ 2 years. Patients with liver iron concentration (LIC) of 2–3, >3–7, >7–14 and >14 mg Fe/g dw were randomized to receive daily DSX 5, 10, 20 and 30 mg/kg or DFO 20–30, 25–35, 35–50 and ≥ 50 mg/kg, respectively. In total, 586 patients received treatment; 299 (51%) were aged

Frequent blood transfusions result in iron overload and lead to life-threatening complications and early mortality if regular chelation therapy (CT) is not implemented. Deferoxamine (DFO), the most common form of CT, requires infusions of 8–12 hours, 5–7 days per week. Deferasirox (DSX) is an oral CT under development. A randomised clinical trial was conducted to compare the safety and efficacy of DFO and DSX. The study demonstrated that at therapeutic doses, DSX is able to maintain/reduce iron burden comparably to DFO. Patient-reported outcomes (PRO) were also collected and are the focus of this analysis. 296 and 290 patients with β-thalassemia were randomised and treated with DSX and DFO, respectively. At baseline, 15 patients had not been treated previously with DFO; these results focus on the 571 patients who had taken DFO previously. DSX was taken orally once per day while DFO was infused via pump for 8–12 hours, 5–7 days per week. Patients who had previously taken DFO were asked at baseline, Week 4, 24 and at the end of the study (EOS) to rate satisfaction with and convenience of DFO or DSX on five-point scales, and indicate the number of hours lost per month while taking CT. At Week 4, patients provided their preferences for either DSX, DFO, or neither. At EOS patients reported whether they would be willing to take the study drug they were on. At baseline, 45% of patients reported that they were either very satisfied or satisfied with DFO taken prior to the study start and 68% reported that DFO was inconvenient or very inconvenient. DFO treatment took approximately 18 hours out of the previous month. At Weeks 4, 24 and EOS, significantly more patients on DSX (92.0%, 89.6%, 85.1%, respectively) reported being very satisfied or satisfied with treatment than patients on DFO (50.4%, 44.0%, 38.7%; p90%), whereas the majority of the DFO group reported DFO to be inconvenient (>60%). Similarly, patients reported 1.3–2.8 hours lost per month due to taking DSX, compared with 3.1–11.7 lost due to taking DFO during the study. 96.9% reported that they preferred DSX to the treatment they were on prior to the study (DFO). The primary reasons for preferring DSX were: more convenient to take (37.4%), less sore than DFO (25.3%), less disruptive to their day (22.8%), less disruptive to their sleep (6.2%) and to their family (4.2%). At EOS, significantly more patients on DSX (85.8%) previously treated with DFO indicated they would be willing to continue DSX, compared with 13.8% of patients on DFO who would be willing to continue DFO. Results suggest that satisfaction and convenience are far superior and the impact on daily activities is less for those on DSX, compared to those on DFO. This has direct implications on patients’ preferences and willingness to continue taking treatments. As compliance to CT has historically been shown to impact survival in transfusion-dependent patients with β-thalassemia major, these data suggest that DSX may significantly improve thalassemia care.

Introduction: Although the direct measurement of iron from a liver biopsy is the reference standard method to determine liver iron concentration (LIC), results are highly unreliable in patients with advanced fibrosis and cirrhosis. As a result, chelation therapy is difficult to monitor in this patient population where effective chelation therapy may be critical. It is therefore important to assess parameters additional to LIC in order to accurately assess body iron in these patients. Aim: To analyze the efficacy of chelation with deferoxamine (DFO) and the investigational once-daily, oral iron chelator deferasirox (DSX) in patients with advanced fibrosis participating in DSX registration studies. Methods: A subgroup of patients from DSX Studies 0107 and 0108 were selected based on a staging result according to the Ischak scale of 5 (incomplete cirrhosis) or 6 (probable or definite cirrhosis), measured either at baseline or after 1 year of chelation therapy. The subgroup of patients with β-thalassemia participating in Study 0107 received DSX (n=26) or DFO (n=30). In Study 0108, the subgroup of patients with β-thalassemia unable to be treated with DFO (n=12) or patients with anemias other than β-thalassemia (n=7) were treated with DSX only. In both studies, patients received chelation therapy according to baseline LIC. Results: In Study 0107, treatment with DSX or DFO led to a decrease in semi-quantitative tissue iron score (TIS) and LIC, which were paralleled by changes in serum ferritin. TIS, LIC and serum ferritin in a subgroup of patients with advanced fibrosis and cirrhosis treated with DSX and DFO (Study 0107) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) DSX (n=26) DFO (n=30) *Median (min, max) Baseline* 35.5 (4,39) 34 (10,52) 25.5 (2.4,45.9) 19.5 (3.9,55.1) 4195 (321,12646) 4144 (653,15283) Change from baseline* −2 (−43,20) −2 (−25,16) −9.4 (−42.2,13.1) −3.1 (−24.5,12.4) −1269 (−7082,3609) −951 (−8259,1264 Similarly, in Study 0108, DSX treatment produced a decrease in all 3 parameters in patients with β-thalassemia or rare anemia. TIS, LIC and serum ferritin in a subgroup of β-thalassemia and rare anemia patients with advanced fibrosis and cirrhosis (Study 0108) TIS LIC, mg Fe/g dw Serum ferritin, ng/mL β-thalassemia (n=12) Rare anemia (n=7) β-thalassemia (n=12) Rare anemia (n=7) -thalassemia β (n=12) Rare anemia (n=7) *Median (min, max) Baseline* 35 (4,48) 41 (32,49) 29.4 (3.8,37.4) 26.3 (15,51.3) 4813 (440,11698) 2385 (1553,9099) Change from baseline* 2 (−19,27) −3 (−20,1) −1.6 (−18,9.9) −10 (−13.9,8.8) −986 (−4453,2131) −1322 (−2609,1901) Conclusions: Chelation therapy with DSX or DFO is effective in reducing iron overload in patients with advanced fibrosis and cirrhosis. The trends observed in TIS and LIC were closely mirrored by changes in serum ferritin, highlighting the validity of this method for monitoring chelation therapy in this population.

Introduction: Direct biochemical measurement of liver iron from biopsy is the reference standard for determining liver iron concentration (LIC) and therefore the efficacy of chelation therapy. Semi-quantitative assessment of liver iron using Prussian blue stained tissue sections has, however, also been shown to correlate with LIC in patients with non-transfusional hemosiderosis. Aim: To determine the value of semi-quantitative liver iron measurement as an indicator of LIC in patients with transfusion-dependent anemia treated with reference standard therapy deferoxamine (DFO) or the investigational once-daily, oral iron chelator deferasirox. The differential involvement of hepatocytes and macrophages in the storage of excess iron was also assessed. Methods: During the deferasirox registration studies, semi-quantitative determination of liver tissue iron score (TIS) was performed in all patients who underwent liver biopsy; these data were compared with other markers of iron overload such as LIC and serum ferritin. In Studies 0107 and 0108, 454 patients with β-thalassemia and 101 patients with β-thalassemia or rare anemias (MDS, DBA and others) underwent liver biopsy at the start of the study and again after 1 year of chelation therapy with deferasirox (Study 0107, n=224 and all patients of 0108) or DFO (Study 0107 only, n=230). Patients analyzed in Study 0108 had β-thalassemia (n=61) or rare anemias (n=40). Results: There was a good correlation between semi-quantitative and quantitative liver iron measurements in all patient populations (R≥0.80, Pearson correlation coefficient). Baseline and change from baseline TIS and LIC are given in Table 1. These changes were dose-dependent, with the greatest decrease observed in patients treated with the highest deferasirox dose (30 mg/kg: TIS decreased from 34.3 ± 7.7 to 25.9 ± 11.2, n=107, in Study 0107; and from 35.3 ± 7.6 to 29.2 ± 10.3, n=78, in Study 0108). Further analyses demonstrated that both deferasirox and DFO were active in removing iron from different functional areas of liver tissue (hepatocytic, sinusoidal and portal areas). Table 1. Overall TIS and LIC changes after 1 year of treatment Study 0107 Study 0108 DFO Deferasirox β-thalassemia Rare anemias (n=230) (n=224) (n=61) (n=40) *Mean ± SD TIS* - Baseline 24.0 ± 10.3 25.3 ± 11.2 29.9 ± 10.9 34.1 ± 9.2 - Change from baseline −2.4 ± 11.2 −3.5 ± 7.1 −4.8 ± 11.2 −6.2 ± 10.1 LIC, mg Fe/g dw* - Baseline 14.5 ± 9.6 15.7 ± 10.1 21.2 ± 10.9 22.8 ± 9.4 - Change from baseline −3.0 ± 8.8 −3.2 ± 5.7 −5.8 ± 9.1 −5.5 ± 7.5 Conclusions: Semi-quantitative iron assessment clearly correlates with quantitative iron measurement. The impact of iron chelation therapy on iron deposits was seen in all functional areas of the liver, with the highest decrease observed in patients treated with deferasirox.

The p210 Bcr-Abl fusion protein is present in virtually all patients with CML and a 185 kD variant is present in approximately 20% of ALL patients. The transforming function of Bcr-Abl requires tyrosine kinase activity of these Bcr-Abl fusion proteins. Thus, Bcr-Abl is an ideal candidate for a molecularly targeted therapeutic agent and an inhibitor of the Bcr-Abl kinase would be predicted to be an effective and selective therapeutic agent for CML. STI571 (formerly CGP57148B), synthesized at Novaris Pharmaceuticals is a potent and specific inhibitor of the Abl kinases and is currently in clinical trials. In a dose-escalating trial all patients in the chronic phase (n=31) have achieved hematologic remissions once therapeutic dose levels were achieved. With prolonged therapy (5 months or greater), a growing fraction of these patients have cytogenetic responses, including several individuals with complete disappearance of the Ph chromosome. STI571 also has remarkable activity as a single agent in CML blast crisis and Ph + ALL patients, however, responses tend not to be durable. As virtually all patients with CML express Bcr-Abl and the Bcr-Abl protein is unique to tumor cells, this disease has provided an ideal opportunity to test the concepts that drugs targeted against a tumor-specific abnormality will have therapeutic utility. Ongoing studies are directed at optimizing the use of this agent.

1. The Australian Committee on Technical and Further Education, Chaired by Mr M. Kangan. This paper examines the decision to form the Interim Committee of Inquiry into Technical and Further Education. In doing so it explores the incremental nature of educational policy‐making in Australia, particularly as it has applied at the federal level. The paper illustrates that the policy process, rather than being goal oriented and rational, is rather a series of adjustments to existing policy, dictated by political expediency, often over many years and changes in governments, which in turn leads to decisions which reflect the instability of their origins. In this case the interim committee which emerged was a consequence of many years of adjustment and realignment of post‐secondary education policy emerging from the federal governments, although the Kangan Committee appears to have emerged almost as an afterthought in the policy process. The decision to appoint the committee was a policy adjustment suited to the ...

One of the major diseases affecting human beings and livestock in Africa, trypanosomiasis—known in its common human form as sleeping sickness—remains resistant to general eradication, a wide belt across the middle of the continent. This is true even though the disease's carriers—several varieties of tsetse flies—and its need for an animal host is well understood. This paper sketches the history of medical, public health, and development concepts that have attempted and achieved short-term and local eradication with a variety of methods, as well as the ecological consequences of these eradication measures, some quite devastating. More ecologically-attuned approaches to development than the simple removal of the tsetse are required in the trypanosomiasis belt if resource degradation and famine are to be avoided.

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Digestion of preparations of insoluble collagen of guinea pig skin with collagenase and trypsin led to the production of two distinct glycopeptide fractions. The lower molecular weight fraction was similar in amount and in composition to the single predominant glycopeptide fraction obtained by similar treatment of soluble collagen. The major component in this fraction had the same chemical and physical characteristics as the glycohexapeptide, Gly-Met-Hyl(-Gal-Glc)-Gly-His-Arg, which had been characterized previously in similar digests of soluble collagen. The second and higher molecular weight glycopeptide fraction (which contained no hydroxylysine) was found only in insoluble collagen. The major amino acids and carbohydrates present in this fraction were aspartic and glutamic acids, glycine, alanine, serine, proline, glucose, galactose, mannose, glucosamine, galactosamine, and sialic acid. The fraction appeared to be quite heterogeneous, and it has not yet been possible to establish whether interpeptide crosslinks were present. This fraction was, however, increased in samples of perchlorate-insoluble collagen identical with those in which Hormann reported evidence for covalent cross-links involving carbohydrate. Alkaline hydrolysis of soluble or insoluble collagen led to the isolation of closely similar quantities of both O-Hyl-(-Gal-Glc) and O-Hyl(-Gal), thus establishing the presence of limited numbers of monosaccharide side chains in both forms of collagen. These analyses, as well as studies of partial acid hydrolysates of purified hydroxylysine-containing glycopeptides, showed the presence in mammalian skin collagen of a disaccharide in which C-1 of D-glucose is linked to D-galactose, and C-1 of D-galactose to the δ-hydroxyl group of hydroxylysine. No evidence was found for the participation of this carbohydrate prosthetic group in crosslinking related to the conversion of soluble collagen to insoluble collagen.