a new era in iron chelation therapy: the design of optimal, individually adjusted iron chelation...
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Hemoglobin, 33(5):332–338, (2009)Copyright © Informa UK Ltd.ISSN: 0363-0269 print/1532-432X onlineDOI: 10.1080/03630260903217182
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LHEM0363-02691532-432XHemoglobin, Vol. 33, No. 5, August 2009: pp. 0–0Hemoglobin
PROCEEDINGS 17TH ICOC
Shenzhen, PR China, November 2007
A NEW ERA IN IRON CHELATION THERAPY: THE DESIGN
OF OPTIMAL, INDIVIDUALLY ADJUSTED IRON CHELATION
THERAPIES FOR THE COMPLETE REMOVAL OF IRON
OVERLOAD IN THALASSEMIA AND OTHER CHRONICALLY
TRANSFUSED PATIENTS
A New Era in Iron Chelation TherapyG.J. Kontoghiorghes
George J. Kontoghiorghes
Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus
� A new era in iron chelation therapy began with the successful removal of excess iron load andthe maintenance of normal iron stores in thalassemia patients using the International Committeeon Chelation (ICOC) protocols. This achievement was based on two phases, firstly the introductionof deferiprone (L1) (80–100 mg/kg/day) and deferoxamine (DFO) (40–60 mg/kg at least 3 daysper week) combination therapy, which appears to progressively remove all excess storage iron andthereafter by the introduction of L1 monotherapy that can maintain physiological range levels ofserum ferritin, cardiac and liver magnetic resonance imaging (MRI) T2*. This new development islikely to change current practices and set a new gold standard in the treatment of transfusional ironloaded patients leading to an increased survival and the change of thalassemia from a fatal to achronic disease. A major aspect of the improved therapies is the ability of L1 to mobilize and removeexcess cardiac iron and reduce congestive cardiac failure, which is the main cause of death inthalassemia patients. Further, new developments include the use of alternating sequential chelationtherapies and selected dose protocols with L1, DFO and deferasirox (DFRA) for overcoming toxicityand efficacy complications observed in some patients treated with monotherapies or combinationtherapies. The selection and adjustment of dose protocols is crucial for providing optimum chelationtherapy for each individual patient.
Keywords Thalassemia, Normal iron stores, Optimal dose protocols, Deferiprone (L1),Deferoxamine (DFO), Deferasirox (DFRA)
Presented at the 17th International Conference on Oral Chelation, Shenzhen, PR China, November23–27, 2007.
Address correspondence to Dr. George J. Kontoghiorghes, Postgraduate Research Institute ofScience, Technology, Environment and Medicine, 3, Ammochostou Street, Limassol 3021, Cyprus; Tel:+35725734915; Fax: +35726272076; E-mail: [email protected]
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A New Era in Iron Chelation Therapy 333
INTRODUCTION
Substantial progress has been made in iron chelation therapy as a resultof the removal of all excess iron load in thalassemia patients following theintroduction of the International Committee on Chelation (ICOC) combi-nation protocol of deferiprone (L1) (80–100 mg/kg/day) and deferoxam-ine (DFO) (40–60 mg/kg at least 3 days per week), which has been shownto achieve normalization of serum ferritin (14–284 μg/L), cardiac (>20 ms)and liver (>6.3 ms) magnetic resonance imaging (MRI) T2* (1,2). Follow-ing the original proposal for the use of L1 and DFO combination in transfu-sional iron overload in 1992, several dose protocols have been tested inthalassemia patients (3). Within this context dose protocols of similar mag-nitude to that of the ICOC protocol described above, appear to have bettereffects in iron removal by comparison to combination protocols of loweroverall doses (4,5).
Following the normalization of the iron stores by the ICOC L1/DFOcombination, L1 monotherapy appears to be sufficient to maintain normalrange levels of serum ferritin, cardiac and liver MRI T2* (6). This findingraises many questions in relation to the ferrikinetics of iron mobilizationduring chelation therapy and the different solubility characteristics of poly-nuclear cores of stored iron, which is variable and depends on the presenceof different levels of excess iron load in transfusional iron overload inthalassemia and other conditions.
There is great variation among patients on efficacy and toxicity duringiron chelation therapy, whether this applies to monotherapies with L1,DFO or deferasirox (DFRA) or the combination therapy of L1 and DFO.Within this context, the efficacy and/or toxicity limitations require thatoptimum chelation therapy is introduced in each patient by selecting themost effective and well tolerated second, third and fourth line chelationprotocol, which can become available for patients having complicationswith the ICOC L1/DFO protocol.
The ultimate aim in iron chelation therapy is the removal of excess ironload and associated toxicity by achieving and maintaining normal level ironstores. If this goal is not possible for some patients, the next most importantaim is the clearance of excess cardiac iron for preventing congestive cardiacfailure, which is the main cause of death in transfusional iron loaded thalas-semia patients. In addition to survival, other parameters should be consid-ered for the selection of the above or other chelation treatments such as thequality of life for each patient and the toxic side effects from chelation orother treatments. Limitations in the use of chelating drugs also apply due tovariations in the availability and cost of chelation therapy in each country andthe overall risk/benefit assessment in each individual patient during thetreatment of the iron loading disease such as thalassemia (7).
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334 G.J. Kontoghiorghes
Availability and Properties of Chelating Drugs Including Factors
Influencing Iron Removal and Excretion
The availability of chelating drugs to thalassemia and other transfusedpatients varies between different countries and depends on many factorsincluding regulatory procedures, government policy, socioeconomic status,marketing policies, etc. (7). For example, L1 has not yet been approved bythe Food and Drug Administration (FDA) and is not available in the USA.In the European Union (EU) all chelating drugs are available and in mostcountries the cost is covered by the governments, e.g., in Cyprus, Greeceand Italy. The high cost of chelating drugs prevents the majority of thalas-semia major patients and other groups of transfusional iron loaded patientsliving in developing countries from receiving adequate chelation therapy. Inmost of these countries all three chelating drugs (L1, DFO and DFRA) areavailable and in most cases the patients have to cover the cost themselves.Marketing pressures from companies and other influences result in highprices and low availability of chelating drugs, despite that both DFO, and L1are generic drugs and the latter can be produced at very low cost (7,8).
Chelators, chelating drugs and their iron complexes have differentphysicochemical, pharmacological and toxicological properties thataffect iron removal. There are also differences in the target organs fromwhere iron is removed and in the route of iron excretion (9). These andmany other parameters can influence the efficacy and toxicity of chelat-ing drugs in each patient, similar to the response of patients to otherdrugs in other diseases.
Many different chelation therapy protocols are used worldwide whichvary with regards to the drug dose, compliance and efficacy, and result indifferent effects on iron removal, general body and organ iron load aswell as associated chelator toxicity (1–5,9–13). Other factors mayalso influence iron excretion since each patient has different drug absorp-tion, distribution, metabolism, elimination and toxicity or tolerance pro-file, resulting in a variable response to the chelating drug or drugcombinations.
The rate of iron accumulation from transfusions, and to a lesserextent, of iron absorption from the gastrointestinal tract, also varies inregularly transfused patients since transfusion requirements, erythro-poietic activity, dietary and other factors affect iron accumulation, tis-sue distribution and excretion (14). Despite that many factors andvariations influence chelation therapy, most patients respond positivelyto the current treatments but at a different level. The selection of opti-mum chelation therapy and of individually adjusted chelation protocolfor each patient is an area which has not yet been fully investigated ordeveloped.
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A New Era in Iron Chelation Therapy 335
Selection of Optimum Individually Adjusted Chelation
Therapy Protocols
The gold standard of iron chelation therapy is the achievement andmaintenance of normal physiological range level iron stores in thalassemiaand other transfusional iron loaded patients (Table 1). Under the presentconditions and available treatments only the ICOC combination protocol ofL1 (80–100 mg/kg/day) and DFO (40–60 mg/kg at least 3 days per week)
TABLE 1 Optimum Iron Chelation Therapy Priorities and Future Goals for Reducing Mortality inThalassemia and Other Transfusional Iron Loaded Patients
First line treatment Suggested therapy
Primary aim is the complete elimination of iron over-load and toxicity. Secondary aim is achievement of normal, physiological range iron stores for preventing iron overload cardiomyopathy, which is the main cause of mortality in transfusional iron overload. Tertiary aim is the prevention of other organ iron overload toxicity, which leads to increased morbidity and mortality other than cardiomyopathy.
Combination of L1 and DFO, e.g., the ICOC L1/DFO combination protocol, until iron stores are normalized, followed by the L1 monotherapy protocol to maintain the normal iron stores.
Second line treatment Suggested therapyIn these cases, the first line treatment of the ICOC com-
bination of L1 and DFO could not be implemented due to toxicity and/or low efficacy by either L1 or DFO. Primary aim is the achievement of normal, physiological range cardiac iron levels for preventing iron overload cardiomyopathy, which is the main cause of death in transfusional iron overload. Every effort should also be made to reduce the total body iron burden.
Combination therapy of L1 and DFO at lower tolerated dose protocols than the ICOC combination protocol. Depending on circumstances, L1 or DFO monotherapy may be used and/or alternating therapies by using sequential administration of each of the two drugs.
Third line treatment Suggested therapyMaximum iron removal in patients where the first and
second line chelation therapy protocols have failed due to toxicity or low efficacy of combinations or monotherapies with L1 and DFO.
Alternating tolerated chelation therapy by using sequential administration of each of the L1, DFO and DFRA monotherapies. Establishment of the most tolerated chelation monotherapy or L1/DFO combination therapy protocol for iron removal from the heart, with a second priority the removal of excess iron from other organs.
Fourth line treatment Suggested therapyMain aim is the maximum iron removal, when the first,
second and third line treatment with L1 and DFO combinations or monotherapies cannot be tolerated due to toxicity.
Deferasirox monotherapy at the maxi-mum approved dose of 30 mg/kg/day. Lower doses of DFRA could be used if the maximum approved dose cannot be tolerated. Deferasirox may also be regularly applied in the future in some patients at a higher dose of 40 mg/kg/day, following approval by the regulatory authorities.
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336 G.J. Kontoghiorghes
has been shown to achieve this goal, i.e., the normalization of serum ferritin(14–284 μg/L), cardiac (>20 ms) and liver (>6.3 ms) MRI T2* levels (1,2).The rate of achieving this goal is variable in each patient and depends onthe initial iron load and the overall dose of the combination. The lower theinitial iron load and the higher the overall chelation combination dose, thefaster the normalization of the iron stores will be (1,2). Within this context,the ICOC L1/DFO combination protocol should be considered as a firstline treatment for all thalassemia and other transfused patients.
Similarly, the L1 monotherapy should be considered as the gold stan-dard for the maintenance of normal iron stores (6). The use of DFO andDFRA is not recommended by the manufacturers in patients with normal orlow level iron stores (low serum ferritin) because of toxicity implications.The dose of L1 (50–100 mg/kg/day) in patients with normal range leveliron stores may vary and be adjusted by regular monitoring of serum fer-ritin levels at monthly or bimonthly intervals. If the levels of serum ferritinare lower than the normal range, the administration of L1 should be tem-porarily stopped and reintroduced at a lower dose, provided serum ferritinexceeds normal range levels. In contrast, if serum ferritin levels are increas-ing, a higher dose of L1 or even the combination therapy with DFO shouldbe temporarily reintroduced but at lower overall doses than the ICOC L1/DFO combination until normal range serum ferritin levels are achieved.
The use of L1 in thalassemia patients is important for reducing morbidityand mortality because it has been shown that it is the only chelator that canrapidly remove excess iron from the heart and increase the prospects of long-term survival, since congestive cardiac failure due to excess cardiac iron loadis the major cause of death in this group of patients (Table 1) (6,10,12,15,16).The maintenance of normal range iron load levels with L1 suggests that che-lation therapy with this drug should be used in young transfused patients asearly as possible in order to avoid the built up of excess stored iron which cancause chronic toxic complications. Unlike present practices, the prospect ofearly treatment with L1 could act prophylactically and reduce the possibilityof long-term organ damage toxicity caused by the chronic accumulation ofexcess iron. The use of this protocol could also result in financial benefitsince the maintenance of normal range level iron stores will require muchlower overall doses of L1 and lower costs. This observation is particularlyimportant for patients in the developing countries where cost is the majorissue for providing any form of treatment and the main reason most patientsare not receiving adequate chelation therapy at present (7,8).
The ICOC L1/DFO combination and L1 monotherapy protocols havebeen tested in groups of patients in the last 8 years with encouraging resultsand low toxicity. However, despite that in most patients the ICOC L1/DFOcombination therapy may be successful, in some other patients there maybe complications including toxicity with either DFO and/or L1. In these
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A New Era in Iron Chelation Therapy 337
cases, a second line treatment of monotherapy with L1 (80–100 mg/kg/day)is recommended for patients experiencing toxicity with DFO, or monother-apy with DFO (40–60 mg/kg at least 5 days per week) for patients experi-encing toxicity with L1 (Table 1). Similarly, in this group of patients, alower L1/DFO combination dose protocol or alternating sequential treat-ment of L1 and DFO, may also be feasible to use depending on theresponse in each patient (Table 1).
In patients facing complications with all three chelating drugs (L1, DFOand DFRA) a third line alternating sequential treatment of two or three ofthe chelating drugs could be used since the toxicity of each of the chelatingdrugs is different, and recovery from the toxic side effects from each mono-therapy in most patients is likely to occur within a short period. For exam-ple, this form of alternating sequential treatment can be used in patientsfacing neutropenia with L1 or increased serum and urine creatinine withDFRA or anaphylactic and other reactions with subcutaneous DFO. Thisalternating form of treatment has been studied in clinical trials comparingtwo chelators, e.g., L1 and DFO without major complications (Table 1)(17). In patients facing complications with both DFO and L1, a fourth linetreatment with DFRA (30 mg/kg/day) is recommended despite that it wassuggested that DFRA should only be used for clinical trials (Table 1) (7,18).
The tolerated dose of each of the chelating treatments described above var-ies in all patients. In each case, the maximum tolerated dose should be used forachieving normal range iron stores or for reaching iron store levels as close tothose of normal individuals as possible. Whatever the outcome in each patient,it is now feasible that by using the ICOC protocols normal range iron levels intransfusional iron loaded thalassemia patients could be achieved and main-tained, something which was unthinkable or had not previously been achievedwith other chelation treatments.
CONCLUSIONS
A new era in iron chelation therapy began with the successful removalof the excess iron load and the maintenance of normal range iron stores inthalassemia patients using the ICOC protocols. This form of treatment iseffective and non toxic in most patients. Alternative, less effective treat-ments are available for patients not responding to the ICOC protocols byusing L1, DFO and DFRA monotherapies, as well as alternating sequentialtherapies by these drugs. Long term randomized clinical trials are neededto confirm the efficacy and low toxicity of the L1/DFO combination and L1monotherapy ICOC combination protocols.
Declaration of Interest: The author report no conflicts of interest. Theauthor alone are responsible for the content and writing of this article.
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