Correspondence

Deferoxamine in Thalassemia Major

N Engl J Med 1995; 332:270-273January 26, 1995

Article

To the Editor:

Brittenham et al. (Sept. 1 issue)1 have shown that early treatment with deferoxamine in patients with thalassemia major can improve survival and reduce the prevalence of major complications of iron overload (such as cardiac impairment). These findings are also of considerable interest with respect to patients undergoing hemodialysis. Notwithstanding the routine use of erythropoietin in the treatment of uremic anemia, the prevalence of iron-overload complications has been reduced but not eliminated in such patients.

In a group of patients with uremia who were undergo-ing maintenance hemodialysis, we found a prevalence of iron overload of 9.6 percent (14 of 146 patients); 4 of the 14 patients had cardiac complications (transient congestive heart failure and arrhythmia). We studied these patients before and after treatment with deferoxamine. Each patient received an infusion of deferoxamine (20 mg per kilogram of body weight) at the end of each hemodialysis session until the ferritin level was lowered to normal (after about three months). At the end of the study, cardiac impairment showed a tendency to recover in concert with the reversal of iron overload (as confirmed by nuclear magnetic resonance imaging).

Since cardiovascular causes account for more than 50 percent of deaths among patients undergoing maintenance hemodialysis,2 we suggest a frequent evaluation of iron status in these patients, whose cardiovascular system is already compromised, in order to prevent further cardiac risk.

Giorgio Splendiani, M.D.
Carmela Tozzo, M.D.
Valentina Mazzarella, M.D
Carlo U. Casciani, M.D.
Tor Vergata University, 00144 Rome, Italy

2 References

1
Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331:567-573
Full Text | Web of Science | Medline

2
Raine AE, Margreiter R, Brunner FP, et al. Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant 1992;7:Suppl 2:7-35
Web of Science | Medline

To the Editor:

Figure 1 of the article by Olivieri et al. (Sept. 1 issue)1 on the survival of medically treated patients with homozygous β-thalassemia presents useful information on the development of cardiac disease in such patients. Unfortunately, this is not the case with Figure 2, which shows that patients whose condition does not deteriorate during treatment do better than those whose condition does deteriorate. Comparisons of survival based on patients' responses to treatment must take into account the time necessary for a response, and this requires either landmark analysis or the conversion of the response variable to a time-dependent covariate, neither of which is described in this paper. Moreover, the statement that the survival rate was 91 percent after 15 years in the group of patients in whom less than 33 percent of ferritin measurements exceeded 2500 ng per milliliter is difficult to understand, since the position of survivors on the curve is not shown and the longest-lived survivor is presumably represented by the data point at 15 years.

Comparison of this statistic with disease-free survival among patients with class I disease as defined by the Pesaro, Italy, bone marrow transplantation group2,3 is impossible, since there were no survivors who were disease-free in the study by Olivieri et al. In the Pesaro study the inclusion of a patient in the analysis of disease-free survival means that the patient no longer has thalassemia. More than 90 percent of these patients visit their physicians once a year to moni-tor their recovery from the complications of pretransplantation therapy, whereas all the “disease-free” survivors in the study by Olivieri et al. have thalassemia and are receiving tedious, expensive, painful, and sometimes ineffective therapy every day.

Although the cost figures given in the paper favor the use of bone marrow transplantation, we do not agree that they represent current costs. However, this point is unimportant, since the cost of disease-free survival is not comparable to the cost of survival with the disease. Therefore, we do not advocate comparing the cost of two therapies, one of which is palliative in intent and outcome and the other of which is curative.

Only a minority of patients with thalassemia have the option of undergoing bone marrow transplantation; most patients must be treated with transfusion and chelation — a treatment that has enormously improved the quality of life of these patients. Given these circumstances, it is a pity that it is so difficult to obtain survival statistics for conventionally treated patients that are based on an intention to treat and include only patients whose current status is known and who are categorized only on the basis of factors known before treatment is started.

G. Lucarelli, M.D.
Ospedale di Pesaro, 61100 Pesaro, Italy

R. Clift, M.L.S.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104-2092

E. Angelucci, M.D.
Ospedale di Pesaro, 61100 Pesaro, Italy

3 References

1
Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous β-thalassemia. N Engl J Med 1994;331:574-578
Full Text | Web of Science | Medline

2
Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in patients with thalassemia. N Engl J Med 1990;322:417-421
Full Text | Web of Science | Medline

3
Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med 1993;329:840-844
Full Text | Web of Science | Medline

To the Editor:

The papers by Brittenham et al. and Olivieri et al. show that daily subcutaneous infusions of deferoxamine reduce the morbidity and mortality caused by transfusion-induced iron overload in patients with severe β-thalassemia. We have obtained similar results in Pavia, Italy, over the past 15 years and agree with the conclusions that deferoxamine treatment should be started early and that a serum ferritin level below 2500 ng per milliliter is a good prognostic indicator. However, in discussing their findings, the authors do not properly address the crucial point of the type of transfusion regimen they adopted.

Pediatricians or hematologists interested in following the current guidelines for the treatment of β-thalassemia major might be referred to a report in Blood 1 or an authoritative book such as Hematology of Infancy and Childhood. 2 These sources suggest that the pretransfusion hemoglobin level should be maintained between 10 and 12 g per deciliter, with a transfusion of 12 to 15 ml of packed red cells per kilogram of body weight given every four weeks in order to raise the hemoglobin level to 15 to 17 g per deciliter. They also state that this regimen of “hypertransfusion” ought to be considered adequate if growth is normal; otherwise, the transfusion regimen should probably be intensified.

Which transfusion regimen was adopted in the two studies showing the efficacy of deferoxamine? Brittenham et al. administered transfusions as needed to raise hemoglobin levels from 8 to 9 g per deciliter to 12 to 14 g per deciliter, whereas Olivieri et al. used a base-line hemoglobin level of 9 g per deciliter as a criterion. Both studies therefore adopted a regimen of “undertransfusion” or moderate transfusion. It should be noted that two of the contributors to these studies were also authors of the guidelines recommending hypertransfusion regimens.

As shown in Table 1Table 1Mean Pretransfusion Hemoglobin Levels and Transfusion Requirements in 31 Patients with b-Thalassemia Major, According to the Transfusion Regimen Used., the type of transfusion regimen used is critical for iron loading. After six years of using a hypertransfusion regimen in a cohort of patients with thalassemia major, we adopted as a criterion a base-line hemoglobin level of 9.5±0.5 g per deciliter (moderate-transfusion regimen). In these patients, the annual volume of blood transfused decreased from 136±28 ml of red cells per kilogram to 102±22 ml of red cells per kilogram (P<0.001); the mean saving was 39 mg of iron per kilogram per year. Chelation therapy was routinely started in each patient after one year of transfusion therapy by administering deferoxamine subcutaneously at a dose of 40 mg per kilogram per day, five to seven days a week. Preliminary data indicate that the percentage of patients with serum ferritin levels below 2500 ng per milliliter increased significantly (P<0.001) after the regimen of moderate transfusion was adopted. Half our patients now have serum ferritin levels below 1000 ng per milliliter, and 93 percent have levels below 2500 ng per milliliter.

We believe that a transfusion program with a base-line hemoglobin level of 9.5±0.5 g per deciliter as a criterion allows a significant reduction in the volume of blood transfused, thus providing better control of iron loading through chelation therapy. Several centers around the world are adopting regimens involving moderate transfusion, although nobody is willing to admit it. There is no reason to be ashamed of this choice. On the contrary, transfusion regimens that may be extremely dangerous for patients with thalassemia, in particular the one using “supertransfusion,” should no longer be recommended. Our final advice is that the use of pretransfusion hemoglobin values of <9 g per deciliter as a criterion should be adopted with caution, since these levels may be associated with insufficient inhibition of erythroid marrow expansion.3

Mario Cazzola, M.D.
Franco Locatelli, M.D.
Piero De Stefano, M.D.
University of Pavia, 27100 Pavia, Italy

3 References

1
Fosburg MT, Nathan DG. Treatment of Cooley's anemia. Blood 1990;76:435-444
Web of Science | Medline

2
McDonagh KT, Nienhuis AW. The thalassemias. In: Nathan DG, Oski FA, eds. Hematology of infancy and childhood. 4th ed. Vol. 1. Philadelphia: W.B. Saunders, 1993:783-879.

3
Cazzola M, De Stefano P, Locatelli F, et al. Relationship between transfusion regimen and suppression of erythropoiesis in β-thalassemia major. Br J Haematol 1994;87:Suppl 1:59-59 abstract.

Author/Editor Response

The authors reply:

To the Editor: We find the description by Lucarelli et al. of our Figure 2 difficult to understand. Our study did not categorize risk “on the basis of factors known before treatment . . . started.” To repeat, we evaluated cardiac disease–free survival in 101 patients with thalassemia. Approximately half these patients maintained low body iron burdens with deferoxamine therapy and had an estimated cardiac disease–free survival of 91 percent. A second group did not maintain reduced body iron stores; their cardiac disease–free survival was less than 50 percent. That deferoxamine reduces body iron to concentrations associated with cardiac disease–free survival was not apparent before this analysis was completed.

Bone marrow transplantation can be offered as therapy to a minority of patients with thalassemia. The majority are concerned with the long-term outcome expected from the only available therapeutic approach — transfusions and iron chelation. We agree that medical therapy and transplantation are not comparable; the former offers survival free of cardiac disease, whereas the latter may provide survival free of thalassemia. Since no definitive information about adverse effects on fertility or other post-chemotherapy complications in patients with thalassemia is available, the statement that transplantation offers disease-free survival is premature.

We agree that transplantation is cost effective (whether or not our figures agree precisely with those in the Pesaro cohort) and that viral hepatitis frequently complicates iron-related fibrosis — a problem that may not be altered by transplantation.1 Our study aimed to establish only that iron chelation reduces the incidence of cardiac disease, the leading cause of death in patients with thalassemia.

Although transplantation yields acceptable results for the patients to whom it is available, in no center on this continent2,3 (and unpublished data) is survival after transplantation for thalassemia equal to that in the Pesaro cohort. Everywhere, of course, patients may die of the complications of either thalassemia or transplantation. Many parents fear losing a child prematurely to a disease that is treatable for decades and for which new approaches may offer promise.4 Therapeutic choices in thalassemia are dictated by the availability of a marrow donor. We are pleased to report that patients do well without transplantation if they can comply with the deferoxamine regimen.

We agree that the use of transfusion to maintain the hemoglobin level above 12 g per deciliter (referred to as “hypertransfusion” by Cazzola et al. and as “supertransfusion” in previous reports) is associated with the administration of increased red-cell volumes. Early short-term studies suggested that the blood volume administered during this regimen would be no larger than that required to maintain lower hemoglobin levels. Clinical practice supports the observations of Cazzola et al. We also agree that a scheme to maintain the pretransfusion hemoglobin level below 9 g per deciliter may aggravate iron loading. We support maintenance of the pretransfusion hemoglobin level between 9 and 10 g per deciliter.

Nancy F. Olivieri, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

David G. Nathan, M.D.
Children's Hospital, Boston, MA 02115

Alan R. Cohen, M.D.
Children's Hospital of Philadelphia, Philadelphia, PA 19104-4399

4 References

1
Lucarelli G, Angelucci E, Giardini C, et al. Fate of iron stores in thalassaemia after bone-marrow transplantation. Lancet 1993;342:1388-1391
CrossRef | Web of Science | Medline

2
Saunders EF, Olivieri N, Freedman MH. Unexpected complications after bone marrow transplantation in transfusion-dependent children. Bone Marrow Transplant 1993;12:Suppl 1:88-90
Web of Science | Medline

3
Walters MC, Sullivan KM, O'Reilly RJ, et al. Bone marrow transplantation for thalassemia: the USA experience. Am J Pediatr Hematol Oncol 1994;16:11-17
Medline