s04 mechanisms of transfusional iron overload toxicity and monitoring of iron overload

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S114 Satellite Symposia S03 Novel TKI therapies for CML: targeting Bcr-Abl with Tasigna M. Talpaz. The University of MichiganCancer Center, USA The development of Imatinib (Glivec, Gleevec) has revolu- tionized the treatment of Chronic Myeloid Leukemia (CML) and pioneered anew era of cancertherapy – Targeted Therapy . Despite the remarkable success of Imatinib, not all patients respondin an optimal manner, failing to achieve a complete cytogeneticresponse,whereas other patients de- velop 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 higherpercentage of patients with advanced disease –the accelerated and blasticphaseswill develop resistance to Imatinibtherapy withinashorterperiod of time. Mechanisms of resistance to Imatinib have been explored in- tensively andit was found that the dominant resistant mecha- nism isthe development of mutation withinthe BCR-ABL ki- nasedomain A TP BINDING POCKET and the flanking areas. This accounts for approximately 50% of the resistant cases. Two novel Tyrosine Kinase Inhibitors (TKIs) have shown re- markable capacity to overcome Imatinibresistance: Dasatinib and Nilotinib (Tasigna). These are two distinct compounds which differsignificantly from each other .Dasatinib isa highly potent compound, but it inhibits multiple targets such as the SRC family of kinases inaddition to the inhibition of BCR-ABL. Nilotinib, on the other hand, is highly specific. It was developed rationally, viathe modification of Imatinib, andit is much less efficient in inhibiting tyrosine kinases such as PDGFR, when compared with Imatinib. Based on these preclinical data, it was predicted that Nilotinibwill be less toxicthan Imatinib. BothDasatinib and Nilotinibwere tested in a large number of Imatinibresistant or intolerant patients and bothhave shown remarkable activity inthese patients. In the chronic phase patients, Dasatinib inducesHematologicResponsein 90% of the patients, and complete cytogeneticresponsein 40% of the patients. Nilotinib was given to 316 CML pa- tients inthe chronicphase. Seventy sevenpercent of these patients achieved complete hematologicremission and 32% gained complete cytogeneticresponse. These are remarkable response rates in patients with long standing disease. The overall tolerance of Nilotinib was remarkably good. Unlike withDasatinib, dose reductions and treatment interruptions were rarely utilized, myelosuppression was modest with an incident of about 50% of that seenwithDasatinib. There were no cases of significant fluid retention, and unlike withDasa- tinib, there were no cases of pleural and pericardial effusions. Nilotinib could be tolerated by virtually all patients whowere taken off Imatinibbecause of severe side effects and poor tolerance. Only hepatic and pancreatic toxicitieswere causes for dose reduction or occasionally treatment discontinuation. Because of its remarkable activity andexcellent 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 effectivein Ima- tinibresistant CML, but neither was effectivein 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 newgeneration of drugs, both specific TKIs anddrugs which lead to the BCR-ABL protein degradation (HSP 90 inhibitors and HDAC inhibitors).All of these newtherapies 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 ex- ists in humans. With repeated transfusions, the iron released from transfused red cells, occurs at such a rate that trans- ferrinbecomes saturated and plasma non-transferrin bound iron (NTBI) is formed, ultimately leading to excess iron accumulation as ferritin andhaemosiderin incertaintissues such as liver, heart, pancreas, anterior pituitary, thyroid, and parathyroid glands. Iron that is not liganded inthe plasma to transferrin or protected withincells by enclosure within ferritin cores is ‘labile’ and capable of participating inthe generation of harmful hydroxyl radicals that damage these tissues. Storageiron withincells is turned over every few days and thus contributes to the magnitude of the poten- tially toxic labileiron pool withincells. The consequences of transfusional iron overload, as well as the benefits of chelation therapy, have beenbest described inthalassaemia major (TM). The highest concentration of storage tissue iron is foundinthe liver, and thisreects total body iron stores. However, heart diseaseisthe 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 inthe pre- chelation areathat 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, magneticresonanceimaging (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 shouldinclude estimation of the rates of iron loading, monitoring of levels of iron burden as well as monitoring for the consequences of excess iron loading inkey targettissues. Levels of iron burden over sustained periods of timeimpact 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, thismeasure correlateswith clinical outcomes

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Page 1: S04 Mechanisms of transfusional iron overload toxicity and monitoring of iron overload

S114 Satellite Symposia

S03 Novel TKI therapies for CML: targetingBcr-Abl with Tasigna

M. Talpaz. The University of Michigan Cancer Center, USA

The development of Imatinib (Glivec, Gleevec) has revolu-tionized the treatment of Chronic Myeloid Leukemia (CML)and pioneered a new era of cancer therapy – TargetedTherapy. Despite the remarkable success of Imatinib, not allpatients respond in an optimal manner, failing to achieve acomplete cytogenetic response, whereas other patients de-velop resistance on therapy. A remarkably low percentage(17%) of newly diagnosed patients develop resistance toImatinib during five years of follow up. However, a muchhigher percentage of patients with advanced disease – theaccelerated and blastic phases will develop resistance toImatinib therapy within a shorter period of time.Mechanisms of resistance to Imatinib have been explored in-tensively and it was found that the dominant resistant mecha-nism is the development of mutation within the BCR-ABL ki-nase 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 re-markable capacity to overcome Imatinib resistance: Dasatiniband Nilotinib (Tasigna). These are two distinct compoundswhich differ significantly from each other. Dasatinib is ahighly potent compound, but it inhibits multiple targets suchas the SRC family of kinases in addition to the inhibition ofBCR-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 suchas PDGFR, when compared with Imatinib. Based on thesepreclinical data, it was predicted that Nilotinib will be lesstoxic than Imatinib.Both Dasatinib and Nilotinib were tested in a large numberof Imatinib resistant or intolerant patients and both haveshown remarkable activity in these patients. In the chronicphase patients, Dasatinib induces Hematologic Response in90% of the patients, and complete cytogenetic response in40% of the patients. Nilotinib was given to 316 CML pa-tients in the chronic phase. Seventy seven percent of thesepatients achieved complete hematologic remission and 32%gained complete cytogenetic response. These are remarkableresponse rates in patients with long standing disease. Theoverall tolerance of Nilotinib was remarkably good. Unlikewith Dasatinib, dose reductions and treatment interruptionswere rarely utilized, myelosuppression was modest with anincident of about 50% of that seen with Dasatinib. There wereno cases of significant fluid retention, and unlike with Dasa-tinib, there were no cases of pleural and pericardial effusions.Nilotinib could be tolerated by virtually all patients who weretaken off Imatinib because of severe side effects and poortolerance. Only hepatic and pancreatic toxicities were causesfor dose reduction or occasionally treatment discontinuation.Because of its remarkable activity and excellent toxicityprofile, Nilotinib may be suitable to be tested in patient withearly disease stage and shortly after diagnosis.

Both second generation TKIs were highly effective in Ima-tinib resistant CML, but neither was effective in CML witha T 315 I BCR-ABL mutation. This Gate Keeper mutationproved to be resistant to current therapy but may respond wellto a new generation of drugs, both specific TKIs and drugswhich lead to the BCR-ABL protein degradation (HSP 90inhibitors and HDAC inhibitors). All of these new therapiesare currently under study.

S04 Mechanisms of transfusional iron overloadtoxicity and monitoring of iron overload

J. Porter. Thalassaemia and Sickle Unit, University CollegeLondon Hospitals, United Kingdom

Repeated blood transfusions inevitably lead to accumulationof body iron load, as each unit contains approximately 200mg of iron and no physiologic iron-excretion mechanism ex-ists in humans. With repeated transfusions, the iron releasedfrom transfused red cells, occurs at such a rate that trans-ferrin becomes saturated and plasma non-transferrin boundiron (NTBI) is formed, ultimately leading to excess ironaccumulation as ferritin and haemosiderin in certain tissuessuch as liver, heart, pancreas, anterior pituitary, thyroid, andparathyroid glands. Iron that is not liganded in the plasmato transferrin or protected within cells by enclosure withinferritin cores is ‘labile’ and capable of participating in thegeneration of harmful hydroxyl radicals that damage thesetissues. Storage iron within cells is turned over every fewdays and thus contributes to the magnitude of the poten-tially toxic labile iron pool within cells. The consequencesof transfusional iron overload, as well as the benefits ofchelation therapy, have been best described in thalassaemiamajor (TM). The highest concentration of storage tissueiron is found in the liver, and this reflects total body ironstores. However, heart disease is the leading cause of deathin patients with TM. In other conditions associated withtransfusional iron overload, the consequences of transfusionaloverload are less clearly defined. However it is known forexample that from postmortem data obtained in the pre-chelation area that increased levels of heart iron are foundafter about 75 units of transfused blood, in direct proportionto transfused unit numbers and to liver iron concentration.Furthermore, magnetic resonance imaging (MRI) data inmyelodysplastic syndromes (MDS) patients show a similarrelationship of myocardial iron to liver iron concentration andto transfusional iron load.Monitoring of iron overload should include estimation of therates of iron loading, monitoring of levels of iron burdenas well as monitoring for the consequences of excess ironloading in key target tissues. Levels of iron burden oversustained periods of time impact on clinical outcomes, andboth serum ferritin (SF) levels and liver iron content (LIC)provide useful estimates of iron burden. Serum ferritin isthe most frequently used measure of iron overload and overthe long term, this measure correlates with clinical outcomes

Page 2: S04 Mechanisms of transfusional iron overload toxicity and monitoring of iron overload

Satellite Symposia S115

and morbidity. Whilst there are broad correlations betweenserum ferritin and LIC, ferritin levels in individual patientsmay not accurately predict the LIC. This is partly becauseserum ferritin levels may fluctuate independently of ironloading, for example rising with inflammation and fallingwith ascorbate deficiency. Thus currently, LIC is consideredthe gold standard for measuring iron overload, accuratelyreflecting total body iron stores. New developments in MRImake it possible to measure LIC non-invasively. Anotherclinically valuable tool that is being used increasingly forestimating iron burden is measuring myocardial T2*: patientswith increased myocardial iron (as shown by a shorting ofthe T2*) are at increased risk of a decreased left ventricularfunction.

Suggested reading

Anderson LJ, Holden S, Davis B, et al. Cardiovascular T2-star (T2*) mag-netic 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 concen-tration and total body iron stores in thalassemia major. N Engl J Med2000;343(5):327-331.

Borgna-Pignatti C, Rugolotto S, De Stefano P, et al, Survival and compli-cations in patients with thalassemia major treated with transfusion anddeferoxamine. Haematologica 2004: 89, 1187-1193.

Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferox-amine in preventing complications of iron overload in patients withthalassemia major. N Engl J Med 1994;331(9):567-573.

Cabantchik ZI. LPI-labile plasma iron in iron overload. Best Pract ResClin Hematol 2005;18:277–287

Davis BA, O’Sullivan C, Jarritt PH, Porter JB. Value of sequential mon-itoring of lef ventricular ejection fraction in the management of tha-lassemia 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 measure-ment and imaging of liver iron concentrations using proton magneticresonance. Blood. 2005;105:855-861.

S05 Chelation therapy in transfusional ironoverload: Exjade efficacy and safety

M.D. Cappellini. Policlinico, Mangiagalli, Regina ElenaFoundation - 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 transfusedblood contains 200–250 mg of iron and the human body hasno mechanism to actively excrete excess iron, cumulative ironoverload is an inevitable consequence of chronic transfusiontherapy. Excess iron in parenchymal tissues can cause seriousclinical sequelae, such as cardiac failure, liver disease, dia-betes and eventual death. Without iron-chelation treatment,the prognosis for patients with iron overload is poor. It hasbeen established that iron chelation therapy reduces the riskfor developing co-morbidities and improves patient survivalduring more than 40 years of clinical experience with the

current reference standard chelator deferoxamine (Desferal®,DFO). One important aim of chelation therapy is to provideconstant, 24-hour protection from the harmful effects of toxiciron (ie NTBI), since gaps in chelation therapy result in ironre-loading and further tissue damage.Deferasirox (!CL670, Exjade) is a new once-daily oral chelat-ing agent developed specifically for the treatment of chroniciron overload. Deferasirox is a tridentate iron chelator, mean-ing that two molecules are required to form a stable complexwith each iron (Fe3+) atom. The active molecule (ICL670) ishighly lipophilic and 99% protein bound. The key chelationproperties of deferasirox are: high and specific affinity forFe3+ (approximately 14 and 21 times greater than its affinityfor copper [Cu2+] and zinc [Zn2+], respectively);oral bioavail-ability; highly efficient and efficacious; effective at multipledoses, allowing flexible regimens; long half-life (8–16 hours),allowing once-daily dosing; generally well tolerated. Thelong 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 programhave demonstrated that the response to deferasirox is not onlydependent on dose, but also on the rate of transfusional ironintake while on study. Although the impact of transfusionrate was underestimated in these studies, it did enable acomparison of various transfusion rates at each dose, leadingto the definition of some general guidance on deferasiroxdosing:• 10 mg/kg/day maintains iron balance in patients with low

transfusional requirements (<2 units of blood/month) andshort history of transfusion

• 20 mg/kg/day maintains or reduces iron balance in patientswith low and intermediate transfusional requirements (2–4units 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 pa-tient’s need based on transfusional requirements, severity ofiron overload and treatment goal (ie maintenance or reductionof body iron levels). The most frequent adverse events (AEs)reported during chronic treatment with deferasirox in clinicaltrials include transient mild-to-moderate gastrointestinal dis-turbances (∼26% of patients) and transient mild-to-moderateskin rash (∼7% of patients). These events rarely required drugdiscontinuation and many resolved spontaneously. Mild, non-progressive increases in serum creatinine (generally withinupper limit of normal [ULN]) were observed in 34% of pa-tients, although these are not currently thought to be clinicallysignificant as they were temporary and reversible. There wereno cases of moderate to severe renal insufficiency or renalfailure and no patients permanently discontinued therapy dueto creatinine rises in the core, 1-year studies. Post-marketingsafety follow-up will be presented.