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S04 Mechanisms of transfusional iron overload toxicity and monitoring of iron overload
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Satellite Symposia
S03 Novel TKI therapies for CML: targeting Bcr-Abl with Tasigna M. Talpaz. The University of Michigan Cancer Center, USA The development of Imatinib (Glivec, Gleevec) has revolutionized the treatment of Chronic Myeloid Leukemia (CML) and pioneered a new era of cancer therapy – Targeted Therapy. Despite the remarkable success of Imatinib, not all patients respond in an optimal manner, failing to achieve a complete cytogenetic response, whereas other patients develop resistance on therapy. A remarkably low percentage (17%) of newly diagnosed patients develop resistance to Imatinib during five years of follow up. However, a much higher percentage of patients with advanced disease – the accelerated and blastic phases will develop resistance to Imatinib therapy within a shorter period of time. Mechanisms of resistance to Imatinib have been explored intensively and it was found that the dominant resistant mechanism is the development of mutation within the BCR-ABL kinase domain ATP BINDING POCKET and the flanking areas. This accounts for approximately 50% of the resistant cases. Two novel Tyrosine Kinase Inhibitors (TKIs) have shown remarkable capacity to overcome Imatinib resistance: Dasatinib and Nilotinib (Tasigna). These are two distinct compounds which differ significantly from each other. Dasatinib is a highly potent compound, but it inhibits multiple targets such as the SRC family of kinases in addition to the inhibition of BCR-ABL. Nilotinib, on the other hand, is highly specific. It was developed rationally, via the modification of Imatinib, and it is much less efficient in inhibiting tyrosine kinases such as PDGFR, when compared with Imatinib. Based on these preclinical data, it was predicted that Nilotinib will be less toxic than Imatinib. Both Dasatinib and Nilotinib were tested in a large number of Imatinib resistant or intolerant patients and both have shown remarkable activity in these patients. In the chronic phase patients, Dasatinib induces Hematologic Response in 90% of the patients, and complete cytogenetic response in 40% of the patients. Nilotinib was given to 316 CML patients in the chronic phase. Seventy seven percent of these patients achieved complete hematologic remission and 32% gained complete cytogenetic response. These are remarkable response rates in patients with long standing disease. The overall tolerance of Nilotinib was remarkably good. Unlike with Dasatinib, dose reductions and treatment interruptions were rarely utilized, myelosuppression was modest with an incident of about 50% of that seen with Dasatinib. There were no cases of significant fluid retention, and unlike with Dasatinib, there were no cases of pleural and pericardial effusions. Nilotinib could be tolerated by virtually all patients who were taken off Imatinib because of severe side effects and poor tolerance. Only hepatic and pancreatic toxicities were causes for dose reduction or occasionally treatment discontinuation. Because of its remarkable activity and excellent toxicity profile, Nilotinib may be suitable to be tested in patient with early disease stage and shortly after diagnosis.
Both second generation TKIs were highly effective in Imatinib resistant CML, but neither was effective in CML with a T 315 I BCR-ABL mutation. This Gate Keeper mutation proved to be resistant to current therapy but may respond well to a new generation of drugs, both specific TKIs and drugs which lead to the BCR-ABL protein degradation (HSP 90 inhibitors and HDAC inhibitors). All of these new therapies are currently under study.
S04 Mechanisms of transfusional iron overload toxicity and monitoring of iron overload J. Porter. Thalassaemia and Sickle Unit, University College London Hospitals, United Kingdom Repeated blood transfusions inevitably lead to accumulation of body iron load, as each unit contains approximately 200 mg of iron and no physiologic iron-excretion mechanism exists in humans. With repeated transfusions, the iron released from transfused red cells, occurs at such a rate that transferrin becomes saturated and plasma non-transferrin bound iron (NTBI) is formed, ultimately leading to excess iron accumulation as ferritin and haemosiderin in certain tissues such as liver, heart, pancreas, anterior pituitary, thyroid, and parathyroid glands. Iron that is not liganded in the plasma to transferrin or protected within cells by enclosure within ferritin cores is ‘labile’ and capable of participating in the generation of harmful hydroxyl radicals that damage these tissues. Storage iron within cells is turned over every few days and thus contributes to the magnitude of the potentially toxic labile iron pool within cells. The consequences of transfusional iron overload, as well as the benefits of chelation therapy, have been best described in thalassaemia major (TM). The highest concentration of storage tissue iron is found in the liver, and this reflects total body iron stores. However, heart disease is the leading cause of death in patients with TM. In other conditions associated with transfusional iron overload, the consequences of transfusional overload are less clearly defined. However it is known for example that from postmortem data obtained in the prechelation area that increased levels of heart iron are found after about 75 units of transfused blood, in direct proportion to transfused unit numbers and to liver iron concentration. Furthermore, magnetic resonance imaging (MRI) data in myelodysplastic syndromes (MDS) patients show a similar relationship of myocardial iron to liver iron concentration and to transfusional iron load. Monitoring of iron overload should include estimation of the rates of iron loading, monitoring of levels of iron burden as well as monitoring for the consequences of excess iron loading in key target tissues. Levels of iron burden over sustained periods of time impact on clinical outcomes, and both serum ferritin (SF) levels and liver iron content (LIC) provide useful estimates of iron burden. Serum ferritin is the most frequently used measure of iron overload and over the long term, this measure correlates with clinical outcomes
Satellite Symposia and morbidity. Whilst there are broad correlations between serum ferritin and LIC, ferritin levels in individual patients may not accurately predict the LIC. This is partly because serum ferritin levels may fluctuate independently of iron loading, for example rising with inflammation and falling with ascorbate deficiency. Thus currently, LIC is considered the gold standard for measuring iron overload, accurately reflecting total body iron stores. New developments in MRI make it possible to measure LIC non-invasively. Another clinically valuable tool that is being used increasingly for estimating iron burden is measuring myocardial T2*: patients with increased myocardial iron (as shown by a shorting of the T2*) are at increased risk of a decreased left ventricular function. Suggested reading Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22(23):2171-2179. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000;343(5):327-331. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al, Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004: 89, 1187-1193. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331(9):567-573. Cabantchik ZI. LPI-labile plasma iron in iron overload. Best Pract Res Clin Hematol 2005;18:277–287 Davis BA, O’Sullivan C, Jarritt PH, Porter JB. Value of sequential monitoring of lef ventricular ejection fraction in the management of thalassemia major. Blood. 2004;104:263-269. Porter JB. Practical management of iron overload. Br J Haematol 2001; 115(2):239-252. St. Pierre TG, Clark PR, Chua-anusom W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005;105:855-861.
S05 Chelation therapy in transfusional iron overload: Exjade efficacy and safety M.D. Cappellini. Policlinico, Mangiagalli, Regina Elena Foundation - University of Milan, Milan, Italy It is well known that red blood cell transfusions are a vital, life-saving treatment for many patients with chronic anemias, including β-thalassemia, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Since every unit of transfused blood contains 200–250 mg of iron and the human body has no mechanism to actively excrete excess iron, cumulative iron overload is an inevitable consequence of chronic transfusion therapy. Excess iron in parenchymal tissues can cause serious clinical sequelae, such as cardiac failure, liver disease, diabetes and eventual death. Without iron-chelation treatment, the prognosis for patients with iron overload is poor. It has been established that iron chelation therapy reduces the risk for developing co-morbidities and improves patient survival during more than 40 years of clinical experience with the
S115
current reference standard chelator deferoxamine (Desferal® , DFO). One important aim of chelation therapy is to provide constant, 24-hour protection from the harmful effects of toxic iron (ie NTBI), since gaps in chelation therapy result in iron re-loading and further tissue damage. Deferasirox (!CL670, Exjade) is a new once-daily oral chelating agent developed specifically for the treatment of chronic iron overload. Deferasirox is a tridentate iron chelator, meaning that two molecules are required to form a stable complex with each iron (Fe3+ ) atom. The active molecule (ICL670) is highly lipophilic and 99% protein bound. The key chelation properties of deferasirox are: high and specific affinity for Fe3+ (approximately 14 and 21 times greater than its affinity for copper [Cu2+ ] and zinc [Zn2+ ], respectively);oral bioavailability; highly efficient and efficacious; effective at multiple doses, allowing flexible regimens; long half-life (8–16 hours), allowing once-daily dosing; generally well tolerated. The long half-life means that deferasirox can be taken once a day (standard dose of 20–30 mg/kg/day). Pooled data from across the deferasirox clinical trial program have demonstrated that the response to deferasirox is not only dependent on dose, but also on the rate of transfusional iron intake while on study. Although the impact of transfusion rate was underestimated in these studies, it did enable a comparison of various transfusion rates at each dose, leading to the definition of some general guidance on deferasirox dosing: • 10 mg/kg/day maintains iron balance in patients with low transfusional requirements (<2 units of blood/month) and short history of transfusion • 20 mg/kg/day maintains or reduces iron balance in patients with low and intermediate transfusional requirements (2–4 units of blood/month) • 30 mg/kg/day decreases iron balance in most patients, irrespective of transfusional requirements. Deferasirox dosing can therefore be tailored to meet a patient’s need based on transfusional requirements, severity of iron overload and treatment goal (ie maintenance or reduction of body iron levels). The most frequent adverse events (AEs) reported during chronic treatment with deferasirox in clinical trials include transient mild-to-moderate gastrointestinal disturbances (∼26% of patients) and transient mild-to-moderate skin rash (∼7% of patients). These events rarely required drug discontinuation and many resolved spontaneously. Mild, nonprogressive increases in serum creatinine (generally within upper limit of normal [ULN]) were observed in 34% of patients, although these are not currently thought to be clinically significant as they were temporary and reversible. There were no cases of moderate to severe renal insufficiency or renal failure and no patients permanently discontinued therapy due to creatinine rises in the core, 1-year studies. Post-marketing safety follow-up will be presented.
Satellite Symposia
S03 Novel TKI therapies for CML: targeting Bcr-Abl with Tasigna M. Talpaz. The University of Michigan Cancer Center, USA The development of Imatinib (Glivec, Gleevec) has revolutionized the treatment of Chronic Myeloid Leukemia (CML) and pioneered a new era of cancer therapy – Targeted Therapy. Despite the remarkable success of Imatinib, not all patients respond in an optimal manner, failing to achieve a complete cytogenetic response, whereas other patients develop resistance on therapy. A remarkably low percentage (17%) of newly diagnosed patients develop resistance to Imatinib during five years of follow up. However, a much higher percentage of patients with advanced disease – the accelerated and blastic phases will develop resistance to Imatinib therapy within a shorter period of time. Mechanisms of resistance to Imatinib have been explored intensively and it was found that the dominant resistant mechanism is the development of mutation within the BCR-ABL kinase domain ATP BINDING POCKET and the flanking areas. This accounts for approximately 50% of the resistant cases. Two novel Tyrosine Kinase Inhibitors (TKIs) have shown remarkable capacity to overcome Imatinib resistance: Dasatinib and Nilotinib (Tasigna). These are two distinct compounds which differ significantly from each other. Dasatinib is a highly potent compound, but it inhibits multiple targets such as the SRC family of kinases in addition to the inhibition of BCR-ABL. Nilotinib, on the other hand, is highly specific. It was developed rationally, via the modification of Imatinib, and it is much less efficient in inhibiting tyrosine kinases such as PDGFR, when compared with Imatinib. Based on these preclinical data, it was predicted that Nilotinib will be less toxic than Imatinib. Both Dasatinib and Nilotinib were tested in a large number of Imatinib resistant or intolerant patients and both have shown remarkable activity in these patients. In the chronic phase patients, Dasatinib induces Hematologic Response in 90% of the patients, and complete cytogenetic response in 40% of the patients. Nilotinib was given to 316 CML patients in the chronic phase. Seventy seven percent of these patients achieved complete hematologic remission and 32% gained complete cytogenetic response. These are remarkable response rates in patients with long standing disease. The overall tolerance of Nilotinib was remarkably good. Unlike with Dasatinib, dose reductions and treatment interruptions were rarely utilized, myelosuppression was modest with an incident of about 50% of that seen with Dasatinib. There were no cases of significant fluid retention, and unlike with Dasatinib, there were no cases of pleural and pericardial effusions. Nilotinib could be tolerated by virtually all patients who were taken off Imatinib because of severe side effects and poor tolerance. Only hepatic and pancreatic toxicities were causes for dose reduction or occasionally treatment discontinuation. Because of its remarkable activity and excellent toxicity profile, Nilotinib may be suitable to be tested in patient with early disease stage and shortly after diagnosis.
Both second generation TKIs were highly effective in Imatinib resistant CML, but neither was effective in CML with a T 315 I BCR-ABL mutation. This Gate Keeper mutation proved to be resistant to current therapy but may respond well to a new generation of drugs, both specific TKIs and drugs which lead to the BCR-ABL protein degradation (HSP 90 inhibitors and HDAC inhibitors). All of these new therapies are currently under study.
S04 Mechanisms of transfusional iron overload toxicity and monitoring of iron overload J. Porter. Thalassaemia and Sickle Unit, University College London Hospitals, United Kingdom Repeated blood transfusions inevitably lead to accumulation of body iron load, as each unit contains approximately 200 mg of iron and no physiologic iron-excretion mechanism exists in humans. With repeated transfusions, the iron released from transfused red cells, occurs at such a rate that transferrin becomes saturated and plasma non-transferrin bound iron (NTBI) is formed, ultimately leading to excess iron accumulation as ferritin and haemosiderin in certain tissues such as liver, heart, pancreas, anterior pituitary, thyroid, and parathyroid glands. Iron that is not liganded in the plasma to transferrin or protected within cells by enclosure within ferritin cores is ‘labile’ and capable of participating in the generation of harmful hydroxyl radicals that damage these tissues. Storage iron within cells is turned over every few days and thus contributes to the magnitude of the potentially toxic labile iron pool within cells. The consequences of transfusional iron overload, as well as the benefits of chelation therapy, have been best described in thalassaemia major (TM). The highest concentration of storage tissue iron is found in the liver, and this reflects total body iron stores. However, heart disease is the leading cause of death in patients with TM. In other conditions associated with transfusional iron overload, the consequences of transfusional overload are less clearly defined. However it is known for example that from postmortem data obtained in the prechelation area that increased levels of heart iron are found after about 75 units of transfused blood, in direct proportion to transfused unit numbers and to liver iron concentration. Furthermore, magnetic resonance imaging (MRI) data in myelodysplastic syndromes (MDS) patients show a similar relationship of myocardial iron to liver iron concentration and to transfusional iron load. Monitoring of iron overload should include estimation of the rates of iron loading, monitoring of levels of iron burden as well as monitoring for the consequences of excess iron loading in key target tissues. Levels of iron burden over sustained periods of time impact on clinical outcomes, and both serum ferritin (SF) levels and liver iron content (LIC) provide useful estimates of iron burden. Serum ferritin is the most frequently used measure of iron overload and over the long term, this measure correlates with clinical outcomes
Satellite Symposia and morbidity. Whilst there are broad correlations between serum ferritin and LIC, ferritin levels in individual patients may not accurately predict the LIC. This is partly because serum ferritin levels may fluctuate independently of iron loading, for example rising with inflammation and falling with ascorbate deficiency. Thus currently, LIC is considered the gold standard for measuring iron overload, accurately reflecting total body iron stores. New developments in MRI make it possible to measure LIC non-invasively. Another clinically valuable tool that is being used increasingly for estimating iron burden is measuring myocardial T2*: patients with increased myocardial iron (as shown by a shorting of the T2*) are at increased risk of a decreased left ventricular function. Suggested reading Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J. 2001;22(23):2171-2179. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000;343(5):327-331. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al, Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004: 89, 1187-1193. Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331(9):567-573. Cabantchik ZI. LPI-labile plasma iron in iron overload. Best Pract Res Clin Hematol 2005;18:277–287 Davis BA, O’Sullivan C, Jarritt PH, Porter JB. Value of sequential monitoring of lef ventricular ejection fraction in the management of thalassemia major. Blood. 2004;104:263-269. Porter JB. Practical management of iron overload. Br J Haematol 2001; 115(2):239-252. St. Pierre TG, Clark PR, Chua-anusom W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005;105:855-861.
S05 Chelation therapy in transfusional iron overload: Exjade efficacy and safety M.D. Cappellini. Policlinico, Mangiagalli, Regina Elena Foundation - University of Milan, Milan, Italy It is well known that red blood cell transfusions are a vital, life-saving treatment for many patients with chronic anemias, including β-thalassemia, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Since every unit of transfused blood contains 200–250 mg of iron and the human body has no mechanism to actively excrete excess iron, cumulative iron overload is an inevitable consequence of chronic transfusion therapy. Excess iron in parenchymal tissues can cause serious clinical sequelae, such as cardiac failure, liver disease, diabetes and eventual death. Without iron-chelation treatment, the prognosis for patients with iron overload is poor. It has been established that iron chelation therapy reduces the risk for developing co-morbidities and improves patient survival during more than 40 years of clinical experience with the
S115
current reference standard chelator deferoxamine (Desferal® , DFO). One important aim of chelation therapy is to provide constant, 24-hour protection from the harmful effects of toxic iron (ie NTBI), since gaps in chelation therapy result in iron re-loading and further tissue damage. Deferasirox (!CL670, Exjade) is a new once-daily oral chelating agent developed specifically for the treatment of chronic iron overload. Deferasirox is a tridentate iron chelator, meaning that two molecules are required to form a stable complex with each iron (Fe3+ ) atom. The active molecule (ICL670) is highly lipophilic and 99% protein bound. The key chelation properties of deferasirox are: high and specific affinity for Fe3+ (approximately 14 and 21 times greater than its affinity for copper [Cu2+ ] and zinc [Zn2+ ], respectively);oral bioavailability; highly efficient and efficacious; effective at multiple doses, allowing flexible regimens; long half-life (8–16 hours), allowing once-daily dosing; generally well tolerated. The long half-life means that deferasirox can be taken once a day (standard dose of 20–30 mg/kg/day). Pooled data from across the deferasirox clinical trial program have demonstrated that the response to deferasirox is not only dependent on dose, but also on the rate of transfusional iron intake while on study. Although the impact of transfusion rate was underestimated in these studies, it did enable a comparison of various transfusion rates at each dose, leading to the definition of some general guidance on deferasirox dosing: • 10 mg/kg/day maintains iron balance in patients with low transfusional requirements (<2 units of blood/month) and short history of transfusion • 20 mg/kg/day maintains or reduces iron balance in patients with low and intermediate transfusional requirements (2–4 units of blood/month) • 30 mg/kg/day decreases iron balance in most patients, irrespective of transfusional requirements. Deferasirox dosing can therefore be tailored to meet a patient’s need based on transfusional requirements, severity of iron overload and treatment goal (ie maintenance or reduction of body iron levels). The most frequent adverse events (AEs) reported during chronic treatment with deferasirox in clinical trials include transient mild-to-moderate gastrointestinal disturbances (∼26% of patients) and transient mild-to-moderate skin rash (∼7% of patients). These events rarely required drug discontinuation and many resolved spontaneously. Mild, nonprogressive increases in serum creatinine (generally within upper limit of normal [ULN]) were observed in 34% of patients, although these are not currently thought to be clinically significant as they were temporary and reversible. There were no cases of moderate to severe renal insufficiency or renal failure and no patients permanently discontinued therapy due to creatinine rises in the core, 1-year studies. Post-marketing safety follow-up will be presented.