combined iron chelation therapy

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Cooley’s Anemia: Ninth Symposium

Combined iron chelation therapy

Renzo Galanello,1 Annalisa Agus,1 Simona Campus,1 Fabrice Danjou,1 Patricia J. Giardina,2

and Robert W. Grady2

1Pediatric Clinic 2, University of Cagliari, Italy and Thalassemia Unit Asl 8. 2Weill Cornell Medical Center, New York,New York

Address for correspondence: Renzo Galanello, Professor of Pediatrics, Pediatric Clinic 2 and Thalassemia Unit Asl8 - University of Cagliari, Via Jenner, 09121 Cagliari, Italy. [email protected]

Patients with thalassemia major accumulate body iron over time as a consequence of continuous red blood cell trans-fusions which cause hepatic, endocrine, and cardiac complications. Despite the availability of three iron chelators,some patients fail to respond adequately to monotherapy with any of them. Combination therapy, consisting in theuse of two chelators on the same day, has been introduced to increase the efficacy and to induce negative iron bal-ance in patients with severe iron overload. Extensive long-term experience has shown that combined chelation withdeferiprone and deferoxamine (DFO) rapidly reduces liver iron, serum ferritin, and myocardial siderosis, improvescardiac function, reverses and prevents endocrine complications, reduces cardiac mortality, and improves survival.Side effects, though significant, are manageable if properly monitored. Preliminary promising results have beenobtained using combined chelation with deferasirox and DFO. As more drug combination regimes are evaluated, itshould be possible to better tailor iron chelation to the needs of the patients, minimizing toxicity and maximizingefficacy throughout life.

Keywords: iron chelation; combined therapy; thalassemia and chelators

Patients with thalassemia major accumulate ironin their bodies as a consequence of continuousred blood cell transfusions. Over time this ironcauses hepatic, endocrine, and cardiac complica-tions. Deferoxamine (DFO) given by regular sub-cutaneous infusion is able to reduce and/or preventiron accumulation, thereby reducing organ dysfunc-tion, morbidity and mortality.1 Endocrine compli-cations are the most common cause of morbidityin patients with thalassemia major. Hypogonadismhas been reported in 35–55% of the patients, hy-pothyroidism in 9–11%, hypoparathyroidism in 4%and diabetes in 6–10%.2,3 Cardiac disease occursin 6–10% of the patients with cardiac failure be-ing the most common cause of death, occurringin more than 70% of the patients.2–4 Low compli-ance with the cumbersome DFO infusions is con-sidered a major factor in the occurrence of thesecomplications. Regulatory approval of the oralchelator deferiprone (DFP) in India in 1995 and inEurope in 1999 was a huge step forward in thetreatment of iron overload. DFP has been shown

to be effective in removing excess iron from the ma-jority of patients receiving regular red cell trans-fusions.5,6 Deferasirox (DFX), recently approvedfor clinical use, is a once-daily oral iron chela-tor with established dose-dependent efficacy inpatients with transfusional iron overload.7 Unfor-tunately, some patients, particularly those with se-vere iron overload, fail to respond adequately tomonotherapy with any of the iron chelators notedabove at the therapeutic doses used most frequentlyto induce negative iron balance. This promptedWonke and colleagues8 to introduce combinationtherapy with DFP and DFO in 1998. In principle, thecombined use of two chelators has several potentialadvantages including higher efficacy, accessibility todifferent iron pools, better tolerability, improvedcompliance, and better management of potentiallytoxic non transferrin bound iron (NTBI). More-over, it should be possible to decrease the dose ofchelator so as to reduce toxicity while maintaininga high chelation efficacy.9 In the literature, the term“combination therapy” has been associated with a

doi: 10.1111/j.1749-6632.2010.05591.xAnn. N.Y. Acad. Sci. 1202 (2010) 79–86 c© 2010 New York Academy of Sciences. 79

Combined iron chelation therapy Galanello et al.

Table 1. Characteristics of currently available iron chelators

Deferoxamine Deferasirox Deferiprone

Route parenteral oral oral

Denticity hexadentate tridentate bidentate

MW ligand 560 373 139

MW complex with iron 619 798 470

Partition coefficient 0.02 6.3 0.18

Protein Binding <10% 99% <10%

Charge positive negative neutral

Volume Distribution small small large

pFe3+ 26 22.5 19

wide variety of chelation regimens. For the sake ofclarity, the term combination therapy should belimited to the coadministration of two chelatorsduring the same day, either simultaneously or se-quentially (e.g., an oral chelator during the day andDFO during the night). Usually the oral chelator istaken every day, while the subcutaneous infusion ofDFO varies from 2 to 7 days per week according tothe severity of iron overload. In patients with heartfailure, DFO can be given intravenously to maxi-mize iron chelation. The term of “alternate chela-tion” should be reserved for regimens where eachchelator is administered on different days (i.e., theoral chelator 3–4 days per week, DFO for the rest ofthe week).

Combined chelation with DFP and DFO

Iron balance studiesThe most relevant pharmacological properties ofDFP and DFO are reported in Table 1. The pharma-cokinetics of the two chelators differ significantly,because of their physicochemical characteristics. Invitro studies have shown that DFP, like other hy-droxypyridones, is able to cross cellular and lyso-somal membranes, whereas DFO is incapable ofcrossing these membranes and enters cells only byendocytosis.10 Therefore, the two chelators seem tohave different tissue distributions and access dif-ferent iron pools. Metabolic iron balance studieshave shown that the concurrent use of DFP andDFO results in an additive or synergistic effect ontotal (urinary and fecal) daily iron excretion11,12

(Fig. 1). “Additive” refers to excretion of an amountof iron equal to the sum of that excreted with eachagent given separately. In some patients, combina-tion of a chelator (DFP) with lower affinity for iron

but a better ability to penetrate cells, with a chelator(DFO) that has a greater affinity but penetrates cellspoorly, may result in a “synergistic” effect (i.e., re-moval of more iron than the sum of that due to eachchelator alone) due to iron shuttling between thetwo compounds. The “shuttle effect,” first proposedby Grady,12 was directly demonstrated by followingthe fate of chelated plasma iron in thalassemic pa-tients receiving combined DFP and DFO.13 DFP ad-ministration produced a temporary accumulationof chelated iron in the plasma after 2 h where-upon the addition of DFO resulted in the trans-fer of chelated iron from DFP to DFO with an in-crease in the total amount of chelated iron in theserum. Shuttling of iron from the bidentate ligand,DFP, to a hexadentate “sink,” DFO, at clinically rel-evant chelator concentrations seems to apply alsoto iron removal from transferrin.14 Together, thesedata suggesting an interaction between DFP andDFO have had important implications for the de-sign of new iron chelation regimens.

Combined chelation with DFX and DFO

Iron balance studiesNow that DFX is used worldwide, it has becomequite clear that many patients fail to respond ad-equately to monotherapy with this drug i.e. theyremain in net positive iron balance. Based on theresults achieved upon combining DFP and DFO,we have recently undertaken an evaluation of DFX(30 mg/kg, p.o., 30 minutes before breakfast) incombination with DFO (40 mg/kg, s.c., over 8 hat night). Unlike DFP, DFX is almost completelybound to proteins in the circulation so it was notobvious that an additive effect would be achieved orthat DFX could shuttle iron to DFO for excretion.

80 Ann. N.Y. Acad. Sci. 1202 (2010) 79–86 c© 2010 New York Academy of Sciences.

Galanello et al. Combined iron chelation therapy

Figure 1. Iron balance studies with DFP+DFO combination therapy. Arrows indicate the two patients in whom combinationtherapy seems to have a synergistic effect.

Three patients have been studied to date employingthe same protocol as that used to evaluate DFP incombination with DFO. Only one patient achievednet negative iron balance on DFX alone while DFOplaced all three in negative balance. When the drugswere given in combination, total excretion was syn-ergistic in two patients (35% and 57% more thanadditive) but less than additive in the third, the pa-tient who responded the best to both drugs individ-ually. Moreover, all of the excess iron appeared inthe urine (2.1- and 3.4-fold increase), strongly sug-gesting that DFX was shuttling extra hepatic iron toDFO. Surprisingly, no increase in urinary iron wasseen in the third patient. While only preliminary,these results add to our optimism that combiningdrugs will prove to be the best approach to ironchelation therapy, a thought reinforced by the re-sults discussed below.

Efficacy of combination with DFP and DFO

Schedule of treatmentOne of the most pressing limitations of the clinicalstudies involving combination therapy is the diffi-culty of comparing results because of differences inthe doses of each drug (DFP, 50–100 mg/kg/day;DFO, 20–60 mg/kg/day), in the number of daysthat DFO is infused (2–7 days per week), and inthe duration of treatment (6–60 months). UsuallyDFO is given as a subcutaneous infusion, but in pa-tients with cardiac failure intravenous administra-tion is often used. Another limitation is that most of

the studies are observational with only a few beingprospective and/or randomized (see later).

Cardiac diseaseAs previously mentioned, a large proportion of pa-tients develop an excessive body iron load despite theavailability of DFO because of difficulties in com-plying with the self-administered subcutaneous in-fusion of the drug. Therefore, it is not surprisingthat chelated patients continue to develop iron in-duced complications, most of them dying from iron-induced cardiac disease.2,15 Using T2∗, a magneticresonance parameter, to measure organ iron load-ing, Tanner and colleagues16 found that myocar-dial iron overload (T2∗ below 20 ms) was presentin 108 (65%) out of 167 adult patients with tha-lassemia major on DFO chelation. The cardiac T2∗

was lower than 8 ms (severe iron overload) in 22 pa-tients (13%). The left ventricular ejection fraction(LVEF) was markedly impaired (<56%) in 62% ofthem. Fifteen of the patients received combinationtherapy with subcutaneous DFO (38 ± 10 mg/kg,5.3 days/week) and daily oral DFP (74 ± 4 mg/kg)for 12 months.17 Their myocardial T2∗ improved(from 5.7 ± 0.9 ms to 7.9 ± 2.4, P = 0.01), with con-comitant improvement in LVEF (from 51.2 ± 10.9%to 65.6 ± 6.7%, P < 0.001).

Origa and colleagues18 also reported an improve-ment in LVEF (from 49 ± 9% to 57% ± 1%,P = 0.001) in 20 patients on combined therapy,no change having been made in their cardiac treat-ment. Moreover, several authors have described

Ann. N.Y. Acad. Sci. 1202 (2010) 79–86 c© 2010 New York Academy of Sciences. 81


successful recoveries from severe heart failure asso-ciated with use of DFP and DFO combination ther-apy in case reports of patients with thalassemia ma-jor as well as with sickle cell anemia and hereditaryhemochromatosis.19–23 In a double-blind, placebo-controlled trial, 65 patients with moderate myocar-dial iron loading (T2∗, 8–20 ms) were randomizedto receive subcutaneous DFO and oral DFP (32 pa-tients) or DFO and placebo (33 patients).24 Therewere significant improvements in the combinedtreatment group compared with the DFO/placebo-treated group. Increases were observed in their my-ocardial T2∗ (ratio of change in geometric means,1.50 vs. 1.24, P = 0.02), absolute LVEF (2.6% vs.0.6%, P = 0.05) and absolute endothelial func-tion quantified by flow mediated dilatation of thebrachial artery (8.8% vs. 3.3%, P = 0.02). Iron-mediated endothelial dysfunction has previouslybeen described in patients with thalassemia ma-jor and linked to increased arterial stiffness.25 Theimprovement associated with combined therapymay be relevant to the management of those pa-tients in whom the interactions between vascula-ture and ventricle are likely to play a significantrole in the development and progression of heartfailure.24

Liver iron concentrationLiver iron concentration has been evaluated in a fewstudies. Tanner and colleagues,17 in their prospec-tive study of patients with severe iron overload andcardiac dysfunction, reported a significant improve-ment of liver T2∗ from a baseline of 3.7 ± 2.9to 10.8 ± 7.3 ms at 12 months (P = 0.006).The same authors, in the randomized, placebo-controlled trial, found a significant improvementof liver T2∗ from a baseline of 4.9 to 10.7 ms at12 months (P = 0.001) in the combined treatmentgroup and from 4.2 to 5.0 ms in the DFO/placebogroup (P = 0.01). The between-group difference(39%) significantly favored the combined treatmentgroup (95% CI, 20–61%, P < 0.001).24 In a clinicalobservational study, combination therapy resultedin the most rapid decline of liver iron concentra-tion compared to monotherapy with DFO, DFP, orDFX.26

A similar significant reduction in liver iron con-tent has been reported in a randomized prospectivestudy carried out to determine the effectiveness ofmild combined therapy (DFP for 7 days and DFO

for 2 days per week), in comparison to monotherapywith the individual drugs.27 In a study of 52 patientstransitioned from DFO to combined therapy, 98%of patients had hepatic iron overload (LIC ≥ 5 mg/gdw), and 64% had severe iron overload at baseline(LIC > 12 mg/g dw). After 3 years of intensive com-bined chelation, these proportions declined to 60and 10%, respectively. By 5 years, none of the 50patients remaining on the study had iron overload.This shift toward a normal hepatic iron load overtime was highly significant (Fisher’s exact test P <

0.001).28

Serum ferritinThe efficacy of combination therapy as assessedby changes in serum ferritin levels has been re-ported in many studies, the results from severalretrospective studies8,16,18,29–38 being summarizedin Figure 2. A reduction in serum ferritin levels wasobserved in all studies but one. In the randomizedplacebo-controlled trial, the mean ferritin level de-clined from 1574 �g/L at baseline to 598 �g/L at12 months (P = 0.001) in the combined group andfrom 1379 to 1146 �g/L (P =0.01) in the DFO groupafter 12 months of therapy. The between group dif-ference was significantly in favor of the combinedtreatment group (–40%; 95% C.I., –48 to –28%; P< 0.001).24 In a group of 52 thalassemia major pa-tients who were switched from DFO monotherapyto combined chelation, serum ferritin declined atthe rate of 85 �g/L per month (P < 0.001).28 After1 year, 53% of the patients had ferritin levels below1000 �g/L, this percentage increasing to 85% after2 years. After 5 years of therapy, 90% of these pa-tients had ferritin values within normal limits (mean87 ± 25 �g/L).28

Urinary iron excretionUrinary iron excretion (UIE) with combinationtherapy has been reported in several studies.Kattamis and colleagues39 observed median UIEsof 0.28 and 0.30 mg/kg/day with DFO and DFPmonotherapy, respectively, and 0.65 mg/kg/dayupon giving the drugs in combination.

In another study the mean UIE during combinedtherapy (0.84 ± 0.48 mg/kg/day) was double thatduring DFO or DFP monotherapy (0.42 ± 0.23 and0.44 ± 0.37 mg/kg/day, respectively, P < 0.0001).18

In 30 patients with thalassemia major, combinationtherapy with DFO and DFP resulted in a median2.3-fold (range 0.28- to 7.35-fold) increase in UIE



Figure 2. Combination therapy clinical studies: changes in ferritin levels.

compared to monotherapy with DFP.40 In all ofthese studies, total absolute iron excretion in re-sponse to combination therapy was even higherbecause fecal iron excretion due to DFO was notaccounted for.

Endocrine complicationsEndocrine complications are a very common fea-ture of beta-thalassemia.3,41 In a study from Greece,reversal of endocrine complications with very inten-sive combined chelation (DFP 75–100 mg/kg/dayand DFO 20–60 mg/kg/day) has been reported.28 Inparticular, abnormal glucose metabolism was nor-malized in 17 (44%) of 39 patients. In 18 patientsrequiring thyroxine supplementation for hypothy-roidism, 10 were able to discontinue therapy and4 others were able to reduce their thyroxine dose.In 14 hypogonadal males on testosterone therapy,7 stopped treatment and quite remarkably, 6 of19 females, who were hypogonadal on DFOmonotherapy, were able to conceive.28

SurvivalTwo studies have reported on survival in patients oncombination therapy. In Cyprus, due to an increas-ing number of cardiac deaths among patients onstandard treatment with DFO, combination therapywas introduced in 1999 for all patients at high risk ofheart failure.42 A multivariate survival analysis wasapplied to this population to test the hypothesis that

survival post-2000 improved relative to that seen be-tween 1980 and 1999. The authors observed a signif-icant upward trend of cardiac deaths between 1980and 2000 (P < 0.001) and a decline after 2000 whenthe patients were switched from DFO monotherapyto combined chelation (P = 0.06). The authors sug-gested that use of combined chelation explained thedecrease in mortality, but could not show this statis-tically due to insufficient data. For this reason, thequestion was readdressed after another two years offollow-up.43 Results of multivariate analysis showedthat combined chelation was the only independentfactor associated with improved survival. None ofthe patients on combination therapy died of cardiacdisease.

A long-term, multicenter, randomized controltrial compared DFO and DFP alone, as well as alter-nating and combined regimens of DFP and DFO.44

After more than 7 years of observation, no deathsoccurred with DFP-alone or the combined use ofDFP and DFO while one death occurred with alter-nating therapy and 10 with DFO monotherapy.

Safety

Combined therapy with DFP and DFO is gener-ally well tolerated; no new or unanticipated ad-verse events have been reported as compared tomonotherapy with either drug.18,27,28,45 The ad-verse events observed in our long-term clinical



Table 2. Adverse events with DFP+DFO combinedchelation: clinical experience at thalassemia unit—Cagliari

Number Occurrence/

of events 100 Pt-years

Neutropenia 14 2.8%

Agranulocytosis 5 1.0%

ALT (transient increase)∗

45 9.0%

Arthropathy 10 2.0%

Gastrointestinal problems 40 8.0%

158 patients/502 patient-years (median = 1.90 years per

patient)

∗A large proportion of the patients were HCV positive.

experience (502 patient-years of observation) arereported in Table 2. Their frequency and severity areno different from those observed in patients on DFPmonotherapy.6 As a single study the incidence ofagranulocytosis, the most important clinically rele-vant side effect of DFP, was higher than that reportedfor DFP alone.18,31,33 However, the cumulative oc-currence of agranulocytosis reported in publishedstudies with combined therapy is not statisticallydifferent from that observed during monotherapytrials of DFP sponsored by ApoPharma (2.2% vs.1.2% in combination vs. DFP monotherapy tri-als, P = 0.4659, Fisher’s exact test; Galanello R,unpublished).

Discussion

Iron overload related complications, as a conse-quence of repeated blood transfusions, are the mostimportant cause of morbidity and mortality in pa-tients with thalassemia major. Although the useof DFO over the past several decades has signifi-cantly reduced the occurrence of these complica-tions, cardiac disease is still the main cause of deathin these patients due largely to poor complianceover time.2,15,45 From the cumulative experiencesreported to date, combined chelation with DFO andDFP seems to be the treatment of choice in orderto achieve a significant decrease in total body ironload, a reduction in iron-related complications andan improvement in survival.

The higher efficacy of combination therapy, ascompared to monotherapy, is easily explained bythe use of two chelators with different tissue distri-butions and affinities for iron, and by the increase in

the total time that the body is exposed to chelation.46

However, apart from the expected additive effect, invitro and metabolic iron balance studies have sug-gested the possibility of synergy between the twochelators, a “shuttle effect” leading to increased ironexcretion.12 Access of the two chelators to differ-ent iron pools would contribute to both additivityand synergy. Strategies and dosing schedules appliedto combination therapy have varied widely, mak-ing comparison of the results somewhat difficult.Overall, however, the results reported confirm theimportance of combination therapy in the manage-ment of severe iron overload. A number of clinicalstudies have concluded that combined therapy offersadditional benefits in terms of reducing cardiac ironloading and improving cardiac function.17,18,20–24,45

The randomized, placebo-controlled study in pa-tients with moderate cardiac iron loading (T2∗, 8–20 ms) and the prospective study in patients withsevere heart iron load (T2∗, less than 8 ms) togetherwith cardiac dysfunction (LVEF below 56%) haveshown that the addition of DFP to DFO therapy re-sults in a significant reduction of myocardial sidero-sis in concert with an improvement in cardiac func-tion. The protective effect on the heart may be due toincreased access of DFP to cardiomyocytes render-ing toxic labile iron metabolically inactive or causingits removal from the cells. Superior cardiac protec-tion in patients treated with DFP monotherapy, ascompared to those on DFO monotherapy, has pre-viously been reported.4,47,48 Of further interest wasthe finding of significant relative improvement inendothelial function in patients treated with com-bined therapy in the placebo-controlled trial.24 En-dothelial dysfunction is likely to play a significantrole in the development and progression of heartdisease in thalassemic patients and its relief mighttherefore be beneficial. Favorable changes in otheroutcome measures have been reported in severalclinical studies, including a reduction in liver ironconcentrations and serum ferritin levels as well asthe reversal of endocrine complications.16,18,24,26–28

The study by Farmaki and colleagues28 suggeststhat intensive chelation may reverse a significantproportion of glucose-related metabolic disorders,hypothyroidism, and hypogonadism in both malesand females.

Observational and prospective randomized stud-ies have shown that combined chelation is able toprevent cardiac mortality and improve survival.42–44



While this might be due to the cardioprotectiveeffect of DFP, it could also be the result of im-proved adherence to the combined treatment. Theuse of questionnaires and close scrutiny of the pa-tients have shown that combination therapy withreduced DFO infusions is accepted by the patientsand results in increased compliance (Galanello, un-published).49 However, continuous assessment ofcompliance is recommended because patients actu-ally take DFP regularly, but reduce their use of DFOover time.45,50 Safety is an issue of major concernfor drugs that patients take lifelong. A relatively highdropout rate has been observed in patients on com-bined therapy because of adverse events.18,42 How-ever, while the adverse events encountered duringcombination therapy may be somewhat more se-vere, they are quite manageable. This highlights theneed for supervision by trained specialists. Partic-ular attention should be paid to the monitoring ofagranulocytosis. It is recommended that the abso-lute neutrophil count be checked every 7–10 days,or at least at each transfusion visit, and that DFPshould be stopped in case of fever and/or signs of in-fection, and immediate medical attention be sought.It is recommended that DFP be permanently with-drawn after an episode of agranulocytosis due to thehigh risk of recurrence (Galanello, unpublished).

Conclusion

Extensive long-term experience has shown thatcombined chelation with DFP and DFO can suc-cessfully be used to treat patients with severe ironoverload. Combined chelation rapidly reduces liveriron and serum ferritin, reduces myocardial sidero-sis, improves cardiac function, reverses and preventsendocrine complications, reduces cardiac mortalityand improves survival. Moreover, it offers more flex-ibility allowing chelation regimes to be tailored tothe needs of the patients. It should also be pointedout that combined chelation has significant butmanageable adverse effects if properly monitored.As more drug combinations are evaluated, it shouldbe possible to refine the design of individualizedchelation regimens so as to minimize toxicity andmaximize efficacy throughout life.

Conflicts of interest

Professor Renzo Galanello has received speaker’shonoraria and research support from Apotex andNovartis.

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