Background The prognosis of patients with homozygous -thalassemia(thalassemia major) has been improved by transfusion and iron-chelationtherapy. We analyzed outcome and prognostic factors among patientsreceiving transfusions and chelation therapy who had reachedthe age at which iron-induced cardiac disease, the most commoncause of death, usually occurs.
Methods Using the duration of life without the need for eitherinotropic or antiarrhythmic drugs as a measure of survival withoutcardiac disease, we studied 97 patients born before 1976 whowere treated with regular transfusions and chelation therapy.We used Cox proportional-hazards analysis to assess the effectof prognostic factors and life-table analysis to estimate freedomfrom cardiac disease over time.
Results Of the 97 patients, 59 (61 percent) had no cardiac disease;36 (37 percent) had cardiac disease, and 18 of them had died.Univariate analysis demonstrated that factors affecting cardiacdisease-free survival were age at the start of chelation therapy(P<0.001), the natural log of the serum ferritin concentrationbefore chelation therapy began (P = 0.01), the mean ferritinconcentration (P<0.001), and the proportion of ferritin measurementsexceeding 2500 ng per milliliter (P<0.001). With stepwiseCox modeling, only the proportion of ferritin measurements exceeding2500 ng per milliliter affected cardiac disease-free survival(P<0.001). Patients in whom less than 33 percent of the serumferritin values exceeded 2500 ng per milliliter had estimatedrates of survival without cardiac disease of 100 percent after10 years of chelation therapy and 91 percent after 15 years.
Conclusions The prognosis for survival without cardiac diseaseis excellent for patients with thalassemia major who receiveregular transfusions and whose serum ferritin concentrationsremain below 2500 ng per milliliter with chelation therapy.
The prognosis of patients with transfusion-dependent homozygous-thalassemia (thalassemia major) has been improved by regulartransfusion and iron-chelation therapy1. Before the introductionof therapy with deferoxamine, an iron-chelating agent, in thelate 1970s,2 iron overload from transfusions was a frequentcause of morbidity and mortality in these patients. Death wasoften due to cardiac failure, which typically began before thepatient reached 20 years of age3. Previous studies have suggestedthat deferoxamine therapy, begun early in life, prolongs survivalwithout cardiac disease,4,5,6,7,8,9 but follow-up was too shortfor unequivocal conclusions. The need for definitive informationabout the long-term prognosis of patients with thalassemia majorhas increased since allogeneic bone marrow transplantation emergedas an alternative treatment10,11,12.
In this report, we present the results of transfusion and chelationtherapy in 97 patients with thalassemia major who were followedat three North American centers. The mean age of the group atthe close of the study was 23 years, an age at which cardiacdisease would be expected in most patients treated only withtransfusions3. The results demonstrate a markedly improved prognosisfor survival without cardiac disease in patients with thalassemiamajor who begin chelation therapy before iron loading is severeand who comply with this treatment regimen.
Methods
Study Design
We examined survival without cardiac disease, which was definedas survival without the need for cardiac inotropic or antiarrhythmicmedication, in all 97 patients with thalassemia major born between1954 and 1975 and treated at three centers: the Hospital forSick Children in Toronto, Children's Hospital in Boston, andthe Children's Hospital of Philadelphia. Pericarditis was notconsidered an outcome measure; no patient in the study had thiscomplication. The ethnic background of the patients was as follows:53 of Italian origin, 30 of Greek origin, 5 of Chinese origin,4 of Indian origin, 3 of Saudi Arabian origin, and 1 each ofLebanese and Turkish origin. Mutations in the -globin gene hadpreviously been characterized in only half the patients. Beginningin 1970, most patients received approximately 15 ml of packedred cells per kilogram of body weight at each transfusion tomaintain hemoglobin levels above 9.0 g per deciliter. They underwentsplenectomy if the volume of packed red cells exceeded 250 mlper kilogram per year. Beginning in 1989, one patient in Bostonreceived red cells separated according to density to enhancethe collection of young erythrocytes (neocytes) with prolongedsurvival in vivo13. Most patients administered deferoxamine(50 to 75 mg per kilogram) to themselves as a nightly 10-to-12-hoursubcutaneous infusion, using standard ambulatory pumps. In Philadelphia,most patients received 2 g of deferoxamine each night regardlessof weight; some patients also received intermittent intravenousinfusions of 4 to 12 g of deferoxamine. Beginning in 1989, 10patients in Toronto received deferoxamine by continuous intravenousinfusion (50 to 80 mg per kilogram per 24 hours)14. No patienthad clinical manifestations of iron-related diabetes mellitus,hypothyroidism, or hypoparathyroidism at the start of deferoxaminetherapy. Patients were followed for a median of 12 years ofdeferoxamine treatment.
At each center, all the patients were interviewed and examinedby a staff physician at intervals of one to six months. Serumferritin concentrations were measured at similar intervals bya standard method15. Cardiac evaluation included an annual historyand physical examination by a cardiologist and annual chestradiography, electrocardiography, and resting echocardiography.Cardiac disease was considered to be present if a patient requiredinotropic drugs (including digoxin) for signs or symptoms ofcardiac failure, therapy for substantial arrhythmias, or both.
Statistical Analysis
For survival without cardiac disease, we considered the followingprognostic factors: clinical center, sex, age at the start oftreatment with deferoxamine, serum ferritin concentration beforechelation therapy, mean serum ferritin concentration, proportionof ferritin measurements exceeding certain threshold values,and degree of reduction in the serum ferritin concentrationapproximately one and two years after therapy began. The meanserum ferritin concentration and the proportion of serum ferritinvalues exceeding a given threshold were used because the timingof serum ferritin measurements was irregular. A window of 10to 18 months was used in estimating the degree of reductionin the serum ferritin concentration at approximately one andtwo years. The mean serum ferritin concentrations and the concentrationsbefore chelation therapy were analyzed on a log scale to reducethe influence of very high values. Cox proportional-hazardsanalysis was used to investigate the effect of each prognosticfactor on survival without cardiac disease. The Cox model withstepwise selection was then used to investigate the joint effectof the prognostic factors. A significance level of 5 percentwas used for the entry of terms, and a level of 10 percent wasused for the removal of terms. P values are given for both univariateand stepwise analyses. The results of Cox modeling have beensummarized with risk ratios for each variable, 95 percent confidenceintervals, and associated P values. Proportions of events arereported relative to the number of patients who could be evaluated.Life-table plots were used to assess disease-free survival overtime.
BMDP-PC90 software programs were used to calculate life-tableestimates of survival without cardiac disease and for Cox modeling(University of California Press, Berkeley). Data manipulationwas performed and descriptive statistics were calculated withthe use of SAS software (version 6.07.01, SAS Institute, Cary,N.C.).
Results
Of 101 patients initially enrolled in the study, 97 could beevaluated. Two patients began treatment at or after the onsetof cardiac disease, and data on serum ferritin concentrationswere unavailable for two other patients. Patients were followedfor a median of 12 years after beginning chelation therapy.The mean (±SD) age of the patients at the close of thestudy in June 1991 was 23 ±5 years.
Table 1 summarizes the patients' clinical characteristics andoutcomes. Fifty-nine patients (61 percent) have no evidenceof cardiac disease at this writing. Thirty-six (37 percent)had cardiac disease, and 18 of them (50 percent) had died. Twopatients died of causes unrelated to cardiac disease; data onthem were included as censored observations in the analysis.Patients without cardiac disease began treatment at an earlierage than those with cardiac disease, had lower mean serum ferritinconcentrations before beginning deferoxamine therapy, maintainedlower mean ferritin concentrations during treatment, and hadlower proportions of ferritin measurements that exceeded thethreshold value of 2500 ng per milliliter during treatment.This proportion became the most important factor predictingdisease-free survival, as discussed below. Transfusion requirementswere similar in patients with and without cardiac disease. Thedifferences in cardiac disease-free survival among ethnic groupswere attributable to the degree of iron loading.
For the full cohort, the estimated survival without cardiacdisease was 80 percent after 5 years of chelation therapy, 65percent after 10 years, and 55 percent after 15 years (Figure 1).As shown in Table 2, factors influencing cardiac disease-freesurvival were age at the start of deferoxamine therapy, serumferritin concentration before treatment, mean serum ferritinconcentration during treatment, and proportion of ferritin measurementsthat exceeded 2500 ng per milliliter during treatment. Withstepwise Cox modeling, only a higher proportion of ferritinmeasurements exceeding this threshold value was associated withpoorer cardiac disease-free survival (risk ratio, 19.1; 95 percentconfidence interval, 6.3 to 58.1; P<0.001).
Table 2. Effect of Prognostic Factors on Survival without Cardiac Disease.
Because some patients had more serum ferritin measurements thanothers, we also evaluated the proportion of measurements exceeding2500 ng per milliliter, using only the first serum ferritindetermination each year. The relation between this variableand cardiac disease-free survival was unchanged.
For patients in whom less than 33 percent of ferritin measurementsexceeded 2500 ng per milliliter, the estimated survival withoutcardiac disease was 100 percent after 10 years of deferoxaminetherapy and 91 percent after 15 years (Figure 2). In contrast,for patients in whom 33 to 67 percent of ferritin measurementsexceeded 2500 ng per milliliter, the estimated disease-freesurvival was 48 percent after 10 and 15 years of therapy. Forpatients in whom more than 67 percent of ferritin measurementsexceeded 2500 ng per milliliter, the estimated disease-freesurvival was 38 percent after 10 years of therapy and 18 percentafter 15 years.
Figure 2. Survival without Cardiac Disease According to the Proportion of Serum Ferritin Measurements Greater Than 2500 ng per Milliliter.
The circles show cardiac disease-free survival among patients in whom less than 33 percent of ferritin measurements exceeded 2500 ng per milliliter; squares show survival among patients in whom 33 to 67 percent of ferritin measurements exceeded 2500 ng per milliliter; and triangles show survival among patients in whom more than 67 percent of ferritin measurements exceeded 2500 ng per milliliter.
Discussion
During the past 10 years, strong evidence of improved survivalwithout cardiac disease in patients with thalassemia major hasaccumulated,4,5,6,7,8,9 and the prognosis appears particularlygood for children with thalassemia born since the current treatmentbecame widely available6. Nonetheless, there are still casesof iron-related illness and death, even in patients who apparentlycomplied with deferoxamine therapy16.
This study describes the outcome of the long-term treatmentof 97 patients with homozygous -thalassemia. Using the end pointof survival without cardiac disease, which we defined as survivalwithout inotropic or antiarrhythmic therapy, we identified factorsrelated to the success or failure of an iron-chelation program.Some of our patients, although they did not need cardiac therapy,may have had early cardiac dysfunction that could have beendetected by methods such as radionuclide angiography. The endpoints in this study may therefore have overestimated disease-freesurvival. Evaluation of the effect of transfusion and chelationtherapy on subclinical cardiac dysfunction must await the developmentof tests with sufficient sensitivity and specificity to predictaccurately the later development of clinical cardiac disease.We could not ethically compare treated and untreated patientsduring the same period. However, one of the last reports ofsurvival in patients with thalassemia before the era of iron-chelationtherapy described the onset of iron-related cardiac failurein 26 of 41 patients (63 percent) at a mean age of 16 years;more than half of the affected patients died of cardiac diseasewithin one year of its onset3. Pericarditis was also frequent,although the relation of this complication to iron overloadremains uncertain3. Our results indicate a markedly improvedoutlook for patients who receive chelation therapy sufficientto maintain a reduced serum ferritin concentration over a longperiod. The favorable outcome of patients who began chelationtherapy in early childhood emphasizes the benefits of treatmentwith deferoxamine.
A sustained reduction in iron, as measured by the proportionof serum ferritin measurements that did not exceed 2500 ng permilliliter, emerged as the most important factor in the survivalwithout cardiac disease among the patients with homozygous -thalassemiawe studied. The estimated disease-free survival 15 years afterthe beginning of chelation therapy was 91 percent among patientsin whom fewer than one third of ferritin measurements exceeded2500 ng per milliliter. Even patients who began chelation therapylater in life but maintained a reduction in their iron storeshad a good prognosis. Conversely, failure to prevent the accumulationof excess iron or to remove large stores of tissue iron wasassociated with a poor prognosis at any age. For example, theprobability of survival after 15 years of chelation therapywas less than 20 percent if more than 67 percent of a patient'sferritin measurements exceeded 2500 ng per milliliter.
Although a single measurement of serum ferritin may be an impreciseassessment of total iron stores,17 serial measurements may beuseful in predicting the likelihood of iron-induced cardiacdisease. Hepatitis C infection, the most common viral complicationof long-term transfusion therapy, may further elevate the serumferritin concentration, complicating its interpretation. Wewere unable to analyze the effect of hepatitis C infection onserum ferritin concentrations because assays to detect hepatitisC antibodies were unavailable during most of the period of investigation.A similar effect of hepatitis C would be expected in patientswith and without cardiac disease, all of whom began transfusiontherapy before donor blood was screened for this infectiousagent.
Our study could not determine the influence of various mutationsof the -globin gene on survival without cardiac disease, becausethe mutations had been characterized in only half the patients.However, any effect of genotype on disease-free survival wouldpresumably be mediated through transfusion requirements, whichdid not differ in patients with and those without cardiac disease.
Chelation therapy has improved survival without cardiac diseasein patients with thalassemia major, but bone marrow transplantationfrom an HLA-identical donor has resulted in thalassemia-freesurvival in many patients. Although we did not compare patientstreated with transfusion and chelation therapy with patientswho underwent bone marrow transplantation, our results providevaluable information for patients, families, and cliniciansfaced with a choice between the two forms of treatment. Patientswith thalassemia major who begin chelation therapy in earlychildhood and most of whose serum ferritin measurements arebelow 2500 ng per milliliter are clinically similar to patientswith class I disease as defined by the Pesaro bone marrow-transplantationgroup11,12. Both groups of patients have benefited from goodmedical care from an early age. The rate of survival withoutcardiac disease in our study (91 percent after 15 years of chelationtherapy) compares favorably with the 3-year disease-free survivalof 85 to 93 percent for patients with class I disease treatedwith bone marrow transplantation12. The poor long-term prognosisof patients who have large iron stores because they cannot getor do not comply with deferoxamine therapy may argue for bonemarrow transplantation, even in the face of hepatic enlargementor fibrosis, which negatively affect the outcome of transplantation11.
Factors other than survival without cardiac disease (for transfusionand chelation therapy) and survival without thalassemia (forbone marrow transplantation) may influence the choice betweenthese treatment options. Cost may be a factor. The estimatedcost (in 1990 dollars) of bone marrow transplantation for hemoglobinopathywas $173,250 in 199118. Additional costs can be anticipatedduring at least the first five years after transplantation19.The cost of transfusion and chelation therapy in a patient whoweighs 30 kg was about $32,000 per year in 1991, with more than60 percent of the cost attributable to chelation therapy18.The cost of medical therapy would be expected to increase asthe patient grew and required more blood and more deferoxamine.The cost of transfusion therapy in some centers is now substantiallyhigher than this estimate and can exceed $30,000 per year inpatients who receive two units of packed red cells every threeweeks (unpublished data). Although the short-term costs of bonemarrow transplantation and transfusion and chelation therapymay be similar, the higher continuing costs of transfusion andchelation may make them the more expensive option.
This study was not designed to establish the optimal serum ferritinconcentration required to prevent iron-related cardiac diseaseor other complications of iron overload. In practice, physiciansstress the importance to their patients of reducing body ironto the lowest possible level. It is possible that maintainingthe serum ferritin concentration considerably below 2500 ngper milliliter may be optimal on a long-term basis, but physiciansmust weigh the benefit of treatment against the toxic effectsof deferoxamine in patients with reduced iron burdens20,21,22,23.Measurements of body iron stores, in addition to the serum ferritinconcentration, may be useful in determining the duration andintensity of chelation therapy24,25.
Supported in part by the Medical Research Council of Canada,the Ontario Heart and Stroke Foundation, General Clinical ResearchCenter grants from the National Institutes of Health (2 M01RR02172-12 and M01 RR00240), and a contract from the Commonwealthof Pennsylvania. Dr. Olivieri and Dr. Koren are Career Scientistsof the Ontario Ministry of Health.
Source Information
From the Hospital for Sick Children (N.F.O., J.H.M., A.M., G.K.) and Toronto Hospital (N.F.O., P.P.L.), University of Toronto, Toronto; the Division of Hematology-Oncology, Children's Hospital and the Dana-Farber Cancer Institute, and the Department of Pediatrics, Harvard Medical School, Boston (D.G.N., A.S.W.); and the Division of Hematology, Children's Hospital of Philadelphia, and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (M.M., A.R.C.).
Address reprint requests to Dr. Olivieri at the Haemoglobinopathy Program, Division of Haematology/Oncology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
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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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Correspondence
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