Efficacy of Deferoxamine in Preventing Complications of Iron Overload in Patients with Thalassemia Major
Gary M. Brittenham, Patricia M. Griffith, Arthur W. Nienhuis, Christine E. McLaren, Neal S. Young, Eben E. Tucker, Christopher J. Allen, David E. Farrell, and John W. Harris
Background To determine whether deferoxamine prevents the complicationsof transfusional iron overload in thalassemia major, we evaluated59 patients (30 were female and 29 male; age range, 7 to 31years) periodically for 4 to 10 years or until death.
Methods At each follow-up visit, we performed a detailed clinicaland laboratory evaluation and measured hepatic iron stores witha noninvasive magnetic device.
Results The body iron burden as assessed by magnetic measurementof hepatic iron stores was closely correlated (R = 0.89, P<0.001)with the ratio of cumulative transfusional iron load to cumulativedeferoxamine use (expressed in millimoles of iron per kilogramof body weight, in relation to grams of deferoxamine per kilogram,transformed into the natural logarithm). Each increase of oneunit in the natural logarithm of the ratio (transfusional ironload to deferoxamine use) was associated with an increased riskof impaired glucose tolerance (relative risk, 19.3; 95 percentconfidence interval, 4.8 to 77.4), diabetes mellitus (relativerisk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiacdisease (relative risk, 9.9; 95 percent confidence interval,1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidenceinterval, 2.4 to 65.4). All nine deaths during the study occurredamong the 23 patients who had begun chelation therapy laterand used less deferoxamine in relation to their transfusionaliron load (P<0.001).
Conclusions The early use of deferoxamine in an amount proportionalto the transfusional iron load reduces the body iron burdenand helps protect against diabetes mellitus, cardiac disease,and early death in patients with thalassemia major.
An adequate transfusion program for patients with thalassemiamajor can prevent death from anemia in infancy and permit normalgrowth and development during childhood. Because the body lacksany effective means for excreting excess iron, transfusion therapyresults in a progressive accumulation of iron, which may beaugmented by iron absorbed from the diet as a result of theincreased ineffective erythropoiesis1. Eventually, extensiveiron-induced injury develops in the liver, pancreas, heart,and other organs. The severity of iron toxicity seems to berelated to the magnitude of the body iron burden2,3. Withouttreatment to remove the excess iron, almost all patients withthalassemia major who regularly undergo transfusions will accumulatetoxic amounts of iron by the age of 10 years or earlier andacquire potentially lethal iron burdens by early adolescence.
Deferoxamine mesylate, a naturally occurring trihydroxamic acidproduced by Streptomyces pilosus, increases urinary iron excretionin patients with thalassemia major4 and is the only iron-chelatingagent approved for clinical use5. Therapeutic trials of deferoxamineadministered intramuscularly,3 intravenously,6 or subcutaneously7have shown that regular chelation therapy can decrease hepaticiron,8 ameliorate cardiac,9,10 pancreatic,11 and other organdysfunction,12,13 improve growth and sexual maturation,14,15and increase survival16,17 in thalassemia major. Although chelationtherapy benefits many patients, others continue to have organdysfunction and die, sometimes despite intensive treatment withdeferoxamine18. The reasons for these apparent differences inthe response to chelation therapy are unknown.
We report here the results of a 10-year prospective study ofpatients with thalassemia major in whom we examined the relationsamong the amount of iron acquired by transfusion before chelationtherapy, the total transfusional iron load accumulated, theamount of deferoxamine administered, the body iron burden asassessed by noninvasive measurements of hepatic iron stores,and clinical outcome as determined by periodic evaluations.
Methods
Patients
We studied 59 patients with thalassemia major (30 of whom werefemale and 29 male, ranging in age from 7 to 31 years when lastseen) who were evaluated periodically in the Clinical HematologyBranch of the National Heart, Lung, and Blood Institute, NationalInstitutes of Health. The patients were given transfusions ofred cells as needed to raise their hemoglobin level from 8 to9 g per deciliter to 12 to 14 g per deciliter. Each patientbegan deferoxamine therapy by the age of four or five yearsor at the time of the initial examination at the National Institutesof Health. The daily dose of deferoxamine prescribed was 1.0g for patients 4 to 7 years old, 1.5 g for those 8 to 12 yearsold, and 2.0 g for those over the age of 12. The average prescribeddose was about 42 mg per kilogram of body weight per day (range,27 to 65), to be taken at least five days each week. The drugwas given by subcutaneous infusion overnight for 8 to 12 hours.Assessment of compliance showed that the patients took 20 to90 percent of the prescribed dose. Two older patients in whomheart disease developed received the drug by continuous intravenousinfusion (3 to 4 g per day) during the last three years of thestudy. This study included only patients for whom there werereliable histories of the number of transfusions received beforethey began deferoxamine therapy and reliable information onthe use of blood products and deferoxamine throughout the study.
Evaluation Procedures
At each follow-up visit, a detailed clinical and laboratoryevaluation included an inventory of the number of transfusionsand the amount of deferoxamine taken since the last visit. Eachunit of blood transfused was considered to contain 4 mmol (225mg) of iron. Pharmacy records were used to confirm the amountsof deferoxamine dispensed. The diagnosis of cardiac diseasewas based on symptoms, physical findings, and the results ofnoninvasive testing, including echocardiography and exerciseradionuclide cineangiography in selected patients. Patientsover 12 years of age who were not known to have abnormal glucosemetabolism were evaluated with an oral glucose-tolerance test.
During the last six years of the study, hepatic iron storeswere measured magnetically with a dual-channel superconductingquantum-interference susceptometer (Biomagnetic Technologies,San Diego, Calif.). This instrument and its validation as amethod of providing measurements of hepatic iron that are quantitativelyequivalent to those obtained by chemical analysis of tissueobtained by liver biopsy have been described elsewhere19,20,21,22.Serum ferritin was measured with a commercial kit (Ramco Laboratories,Houston).
Statistical Analysis
The Fisher-Irwin exact test was used to compare the proportionsof patients in two groups formed with the use of dichotomousvariables23. Multiple regression models were formed to determinethe subgroup of independent variables most predictive of a dependentvariable. Differences in the survival of groups were evaluatedwith the Kaplan-Meier product-limit method and the log-ranktest24,25. Cox proportional-hazards regression with the likelihood-ratiotest and the Wald statistic was used to investigate the effectof several variables on survival26,27. The proportional-hazardsassumption was examined with use of Schoenfeld residuals28.The BMDP and S-Plus statistical computer packages were usedfor computations. All tests were two-tailed; a P value of 0.01was considered to indicate statistical significance.
Results
Follow-up of the 59 patients with thalassemia major produceda cumulative total of 440 patient-years of observation. Allthe patients had been dependent on transfusions since infancy.
Magnetic Measurements of Hepatic Iron Stores
The body iron burden was assessed in 53 patients by noninvasivemagnetic measurements of liver iron stores. Six patients diedbefore this method became available. Hepatic iron concentrationsranged from nearly normal to more than 175 µmol of ironper gram of liver tissue (wet weight) (normal, 1 to 9)19. Toevaluate the effectiveness of deferoxamine in reducing the bodyiron burden, we examined the relation between the value determinedby magnetic measurement and the ratio of the total transfusionaliron load to the amount of deferoxamine used (expressed in millimolesof iron per kilogram, in relation to grams of deferoxamine perkilogram). As shown in Figure 1, the ratio of transfusionaliron load to deferoxamine use, expressed in logarithmic form,correlated closely with the hepatic iron concentration (Pearson'sR = 0.89, P<0.001). Multiple regression analysis demonstratedan independent effect of deferoxamine use on hepatic iron stores,both when deferoxamine use was considered alone and when itwas considered as a variable interacting with the transfusionaliron load (i.e., as part of the ratio) (P<0.001 for eachcomparison). Regression analysis also revealed that 79 percentof the variation in hepatic iron concentrations could be explainedby the variation in total transfusional iron and the ratio ofthe transfusional iron load to deferoxamine use. This resultprovided evidence of the accuracy of the data on iron from transfusionsand on deferoxamine use.
Figure 1. Relation between Hepatic Iron Concentration and the Ratio of the Total Transfusional Iron Load to Cumulative Deferoxamine Use in 53 Patients with Thalassemia Major.
The diagonal line is the simple linear least-squares regression line between the two variables. The ratio, determined in millimoles of iron and grams of deferoxamine, is expressed as a natural logarithm.
Serum ferritin concentrations correlated significantly withmagnetic measurements of hepatic iron stores in 52 patients(R = 0.72). Overall, the ferritin concentrations qualitativelyreflected differences found on direct measurement of hepaticiron stores by magnetic means, but the concentrations of individualpatients showed considerable fluctuations that were independentof changes in body iron stores21.
Complications of Deferoxamine Therapy
Although most patients reported some local irritation and swellingafter subcutaneous infusions of deferoxamine, none of thesepatients had visual or auditory symptoms of neurotoxicity29or of the pulmonary syndrome reported in association with intravenousadministration of deferoxamine at doses of 10 g per day or more30.No other complications of deferoxamine therapy were observed.
Glucose Metabolism
Glucose tolerance was evaluated in 54 patients who were over12 years of age: insulin-dependent diabetes mellitus was foundin 11 patients (20 percent), and glucose tolerance was impairedin 6 others (11 percent).
Cardiac Disease and Death
On enrollment, 2 of the 59 patients had heart disease that wasnot the result of uncomplicated iron overload and were excludedfrom further analysis of cardiac complications. Three of theremaining patients already had heart disease that was clinicallyconsidered due to iron overload: one patient had a history ofpericarditis, the second had a history of transient congestiveheart failure, and the third had an asymptomatic arrhythmia.Of the 54 patients initially free of heart disease, 12 (22 percent)later had cardiac dysfunction. Of the 57 patients evaluatedfor cardiac complications, 9 (16 percent) died; 2 of these alreadyhad heart disease at entry. Cardiac disease was the cause ofdeath or a major contributor to the cause of death in all thepatients who died. Clinical evidence of cardiac dysfunctionin the six surviving patients was documented by noninvasivetesting. The characteristics of the 15 patients who died orhad cardiac disease due to iron overload are shown in Table 1.
Table 1. Characteristics of the Patients Who Died or Had Heart Disease.
Effect of Transfusional Iron Loading and Deferoxamine Use on Clinical Outcome
To assess the independent effect of deferoxamine on the relativerisk of death, a proportional-hazards model was constructedin which age, transfusional iron load before the initiationof chelation therapy with deferoxamine, transfusional iron loadafter the initiation of deferoxamine therapy, and cumulativedeferoxamine dose were used as predictor variables. The independenteffect of deferoxamine remained significant after adjustmentfor the other predictors (P = 0.007). To assess the effect ofdeferoxamine when expressed as an interaction (i.e., as a ratio),a second model was constructed in which age, transfusional ironload before deferoxamine, transfusional iron load after deferoxamine,and the natural logarithm of the ratio of the total transfusionaliron load to deferoxamine use were used as predictor variables.The effect of deferoxamine remained strong when expressed interms of its interaction with the total transfusional iron load(P = 0.007). In this model, the estimated relative risk of deathassociated with an increase in the ratio of transfusional ironload to deferoxamine use was 12.6 (95 percent confidence interval,2.4 to 65.4), implying that an increase of one unit in the naturallogarithm of this ratio would increase the risk of death 12.6times. Similar analyses were performed for the variables ofimpaired glucose tolerance, diabetes mellitus, and cardiac disease.The estimated relative risk of impaired glucose tolerance associatedwith an increase in the ratio of the transfusional iron loadto deferoxamine use was 19.3 (95 percent confidence interval,4.8 to 77.4), the relative risk of diabetes mellitus was 9.2(95 percent confidence interval, 1.8 to 47.7), and the relativerisk of cardiac disease was 9.9 (95 percent confidence interval,1.9 to 51.2).
Clinical outcome was also examined after the patients were classifiedinto four groups according to the pretreatment iron load andthe amount of deferoxamine administered. The group of patientswith the highest iron load before deferoxamine treatment andthe lowest use of deferoxamine in relation to their total transfusionaliron load was designated as group 1. The remainder of the patientswere designated as group 2, which was subdivided into groups2A, 2B, and 2C as shown in Table 2. Data on the four groupswith respect to the transfusional iron load before chelationtherapy and the ratio of the total transfusional iron load tocumulative deferoxamine use are summarized in Table 3; the distributionof the patients among these groups is shown in Figure 2.
Table 2. Grouping of Patients According to Their Transfusional Iron Load before Chelation Therapy with Deferoxamine and the Effectiveness of Chelation.
Figure 2. Relation between the Transfusional Iron Load before Deferoxamine Therapy and the Ratio of the Total Transfusional Iron Load to Cumulative Deferoxamine Use in 59 Patients with Thalassemia Major.
The vertical line denotes the geometric mean for the pretreatment iron load (14 mmol of iron per kilogram of body weight), and the horizontal line the geometric mean for the ratio (0.6 mmol of iron per gram of deferoxamine, expressed as a natural logarithm). The solid circles denote the nine patients who died during the study, and the open circles the surviving patients at their most recent evaluation. The means were used to group the patients (groups 1, 2A, 2B, and 2C are defined in the Results section, with details in Table 2 and Table 3).
To examine further the effects of transfusional iron loadingand deferoxamine use on clinical outcome, the 23 patients withthe highest transfusional iron load and the lowest deferoxamineuse (group 1) were compared with the remaining 36 patients (group2). The body iron burden of group 2, as assessed by measurementof the mean hepatic iron concentration, was less than half thatof group 1 (53 vs. 119 µmol of iron per gram of liver,wet weight; P<0.001). In addition, group 2 had a lower prevalenceof cardiac disease (P<0.001), impaired glucose tolerance(P<0.001), and insulin-dependent diabetes mellitus (P = 0.01)that developed during the study (Table 3). All of the nine patientswho died during the study belonged to group 1 (P<0.001).In this group, the probability of survival to at least the ageof 25 years was 32 percent (95 percent confidence interval,4 to 59 percent) (Figure 3). When survival in group 1 over the10 years of the study was compared with that in group 2, survival(adjusted for age) was significantly better in group 2 (L =10.04, P = 0.0015 by log-rank test).
Figure 3. Life-Table Analysis of the Survival of the 38 Patients in Groups 1 and 2 Who Were 15 Years of Age or Older at Their Most Recent Evaluation.
Age-adjusted survival analysis indicated that the cumulative probability of survival to at least the age of 25 years was 32 percent (95 percent confidence interval, 4 to 60 percent) in group 1. A comparison of the survival distributions in the two groups over the 10 years of the study showed that survival was significantly better in group 2 (L = 10.04, P = 0.0015 by log-rank test).
To examine factors associated with the observed differencesin clinical outcome, group 2 was divided according to the transfusionaliron load before the initiation of chelation therapy with deferoxamine:patients in group 2A had high pretreatment iron loads and effectivechelation therapy, and those in group 2B had low pretreatmentiron loads and effective chelation therapy. Group 2C includedonly two patients, who had low pretreatment iron loads and ineffectivechelation and who have been omitted from the comparisons presentedbelow. As shown in Figure 4, the mean ratios of the total transfusionaliron load to deferoxamine use and the hepatic iron concentrationsof groups 2A and 2B were similar (Table 3). There were no deathsin these groups and no significant differences between themin the prevalence of cardiac disease, impaired glucose tolerance,or diabetes mellitus (Table 3). Thus, differences in the prevalencesof clinical complications in groups 1 and 2 could not be attributedto the inclusion in group 2 of patients (group 2B) who had lowertransfusional iron loads before beginning deferoxamine therapythan the patients in group 1.
Figure 4. Mean (±SE) Age, Iron Loading, Deferoxamine Use, and Ferritin Levels in Groups 1, 2A, and 2B.
The bars represent the patients' ages, transfusional iron loads before chelation therapy with deferoxamine, cumulative transfusional iron loads, cumulative deferoxamine use, magnetically determined hepatic iron concentrations, and plasma ferritin concentrations. The groups are defined in the Results section.
The patients in groups 1 and 2A, who had similar transfusionaliron loads before the start of deferoxamine therapy but differentratios of the total transfusional iron load to deferoxamineuse (Table 3), did not differ significantly in age, transfusionaliron load before deferoxamine, or total transfusional iron loadafter the start of deferoxamine treatment (Figure 4). The groupsdid differ with respect to chelation therapy; on average, thepatients in group 2A used more than twice as much deferoxamineas those in group 1 (P<0.001) (Figure 4). The greater cumulativeuse of deferoxamine correlated with a substantial decrease inthe body iron burden: the mean hepatic iron concentration inthe patients in group 2A was less than half that in the patientsin group 1 (P<0.001) (Figure 4). Groups 1 and 2A also differedsignificantly in clinical outcome: group 2A had a lower prevalenceof impaired glucose tolerance (P = 0.009) and cardiac disease(P = 0.001) (Table 3). There were no deaths in group 2A, ascompared with nine deaths in group 1 (P = 0.01).
Discussion
We studied 59 patients with thalassemia major treated with regularparenteral infusions of deferoxamine for transfusional ironoverload over a 10-year period. When each patient entered thestudy and periodically thereafter, we performed a clinical evaluationand obtained a detailed accounting of the number of transfusionsreceived and the amount of deferoxamine administered. As partof the clinical evaluation during the last six years of thestudy, body iron burden was assessed with direct, noninvasive,magnetic measurements of hepatic iron stores. Measurement ofhepatic iron is the most quantitative means of assessing thebody iron burden in patients with thalassemia major31.
We found that the concentration of iron in the liver correlatedclosely (R = 0.89, P<0.001) with the ratio of the total transfusionaliron load to cumulative deferoxamine use, expressed as a naturallogarithm (Figure 1). For a given total transfusional iron load,the principal determinant of body iron burden was the cumulativedose of deferoxamine that had been administered. Multiple regressionanalysis showed that the independent effect of deferoxamineadministration in reducing hepatic iron stores was significant(P<0.001).
In evaluating factors influencing clinical outcome, we consideredboth the ratio of the total transfusional iron load to cumulativedeferoxamine use and the extent of transfusional iron loadingat the initiation of chelation therapy. The first factor providesa measure of the use of deferoxamine relative to the total transfusionaliron, whereas the second provides a measure of the transfusionaliron load before the start of deferoxamine therapy. Cox proportional-hazardsregression analysis, with adjustments for age and the transfusionaliron load before deferoxamine therapy, was used to estimatethe increase in the relative risk of complications associatedwith each increase of one unit in the ratio of the transfusionaliron load to deferoxamine use. Before one examines the results,one should put the magnitude of a difference of one unit inthe natural logarithm of the ratio in clinical perspective byusing regression analysis to estimate the corresponding hepaticiron concentrations and serum ferritin concentrations in thepatients studied, also taking into account the considerablefluctuations in serum ferritin concentrations that occur independentlyof changes in body iron stores21. According to these approximations,a patient with a ratio of 2.8 would be expected to have a hepaticiron concentration of about 25 µmol of iron per gram ofliver (wet weight) (1400 µg of iron per gram) and a serumferritin concentration of about 900 ng per milliliter. For comparison,a patient with an increase of one unit in the ratio, to 3.8,would have an estimated hepatic iron concentration of about100 µmol of iron per gram of liver (5700 µg of ironper gram) and a serum ferritin concentration of about 3800 ngper milliliter.
Proportional-hazards analysis showed that each increase of oneunit in the natural logarithm of the ratio of the total transfusionaliron load to deferoxamine use was associated with a substantialincrease in the relative risk of impaired glucose tolerance(19.3), diabetes mellitus (9.2), cardiac disease (9.9), anddeath (12.6); the analysis also showed that the independenteffect of deferoxamine therapy in decreasing the relative riskof death was significant (P = 0.007). Together, the resultsof magnetic measurements of hepatic iron stores and proportional-hazardsanalysis indicated that greater use of deferoxamine in relationto the transfusional iron load effectively decreased the bodyiron burden and reduced the risk of impaired glucose tolerance,diabetes mellitus, cardiac disease, and death.
We reached similar conclusions by classifying the patients intoclinically recognizable groups. Together, the ratio of the totaltransfusional iron load to deferoxamine use and the transfusionaliron load before deferoxamine therapy were used to identifya group of 23 patients (group 1) who had the highest pretreatmentiron loads and the lowest use of deferoxamine in relation totheir total transfusional iron loads. This group had the highestrisk of clinical complications and death. Indeed, all nine deathsoccurred among these patients, who had begun chelation treatmentlater and used less deferoxamine in relation to their transfusionaliron load than did the other groups (P<0.001). The cumulativeprobability of survival to at least the age of 25 years wasonly 32 percent (95 percent confidence interval, 4 to 59 percent)in group 1. The remaining 36 patients (group 2), with earlieror greater use of deferoxamine, had fewer complications associatedwith iron overload, and none died. These associations remainedsignificant when the analysis was restricted to patients whohad large transfusional iron loads before the initiation ofchelation therapy but differed in their ratios of total transfusionaliron load to deferoxamine use -- that is, groups 1 and 2A. Thesecomparisons suggest that the patients in group 1 had higherbody iron burdens not because they had greater transfusionaliron loads but because they used less deferoxamine.
These findings indicate that patients with thalassemia majorwho have the greatest risk of early death and clinical complicationsare those with high body iron burdens resulting from inadequatetreatment with deferoxamine. Our evidence shows that early administrationof deferoxamine in amounts proportional to the transfusionaliron load effectively reduces the body iron burden of thesepatients and helps protect them against major complicationsand early death. Both the risks posed by insufficient chelationtherapy and the benefits of adequate deferoxamine use meritconsideration in patients in whom bone marrow transplantationis contemplated,32 as well as in clinical trials of oral chelatingagents5.
Supported in part by research grants from the Cooley's AnemiaFoundation, the Food and Drug Administration (FD-U-000532),and the National Institutes of Health (AM-25105, DK-14370, HL-24198,and HL-42814).
Source Information
From the Departments of Medicine (G.M.B., J.W.H.) and Physics (C.J.A., D.E.F.), Case Western Reserve University, Cleveland; the Department of Mathematics, Moorhead State University, Moorhead, Minn. (C.E.M.); St. Jude Children's Research Hospital, Memphis, Tenn. (A.W.N.); and the Clinical Hematology Branch (P.M.G., N.S.Y.) and Cardiology Branch (E.E.T.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Address reprint requests to Dr. Brittenham at MetroHealth Medical Center, 3395 Scranton Rd., Cleveland, OH 44109.
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Deferoxamine in Thalassemia Major
Splendiani G., Tozzo C., Mazzarella V., Casciani C. U., Lucarelli G., Clift R., Angelucci E., Cazzola M., Locatelli F., De Stefano P., Olivieri N. F., Nathan D. G., Cohen A. R.
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N Engl J Med 1995;
332:270-273, Jan 26, 1995.
Correspondence
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