Original Article
Brief Report
Treatment with Azacitidine of Patients with End-Stage β-Thalassemia
N Engl J Med 1993; 329:845-848September 16, 1993
- Article
Regular erythrocyte transfusions form the cornerstone of treatment for patients with severe β-thalassemia. Despite the use of iron-chelation therapy, fatal iron overload develops in many patients, even when they are under supervision and taking part in studies designed to test the effectiveness of intense chelation1,2. Another potential consequence of long-term transfusions is the development of antierythrocyte antibodies, making effective transfusion difficult or, in rare cases, impossible3-6.
A potential alternative to transfusion is the use of the nucleoside analogue azacitidine to stimulate transcription of the fetal globin genes by pharmacologic means and thus lead to more effective erythropoiesis7-12. Although the mechanism of this effect is not well understood, it is believed to be related in part to the ability of the drug to inhibit methylation of newly synthesized DNA within regions that regulate the expression of globin genes7,8,12,13. Recent work shows that a previously identified site of azacitidine-induced hypomethylation within the promoters of the fetal globin genes coincides with a DNA sequence that binds proteins participating in the switch from the expression of fetal to that of adult globin genes7,14. Azacitidine may also enhance fetal globin synthesis through its effect on the kinetics of erythroid-precursor maturation15,16.
We describe the effect of azacitidine treatment in three patients with end-stage β-thalassemia for whom continued transfusion therapy was no longer beneficial. Treatment freed all three patients from the need for transfusions. Two patients have thus far been treated for 30 months, with improvement in their clinical status and quality of life.
Methods
The protocol was approved by the institutional review board of the National Heart, Lung, and Blood Institute. Patients gave informed consent before beginning treatment. Azacitidine was administered at an initial dose of 2 mg per kilogram of body weight per day by continuous intravenous infusion for four days at two- to four-week intervals. The drug was freshly prepared in lactated Ringer's solution every four hours17. Patients received oral antiemetic prophylaxis during treatment. Blood counts were monitored every other day during the drug infusions and weekly between treatments. Laboratory evaluation of hepatic and renal status was performed before each treatment cycle. Otherwise, patients received routine care for their thalassemia. Statistical analysis was by the t-test.
Case Reports
Patient 1
Patient 1 was a 50-year-old man with β-thalassemia intermedia and a hemoglobin level of 6.2 g per deciliter in the absence of transfusion. At the age of 41 he participated in early trials of azacitidine, responding with increased hemoglobin levels after short courses of treatment7,10. The final course was complicated by a disseminated fungal infection with Cunninghamella bertholletiae18. When the patient was in his mid-40s, severe iron overload developed with testicular failure, hepatic iron stores exceeding 6000 μg of iron per gram of liver,19 and cardiac hemochromatosis, as evidenced by ventricular ectopy and abnormal left ventricular function. Despite the initiation of daily intravenous infusions of deferoxamine, the patient's condition worsened, and at the age of 48 he was found to have congestive heart failure requiring admission to the intensive care unit. His cardiac ejection fraction was 16 percent on admission.
Patient 2
Patient 2 was a 30-year-old woman with β-thalassemia major who had required transfusions since the age of 7 years. In the several months before treatment with azacitidine was begun, her local blood bank had been unable to find erythrocytes suitable for transfusion. Evaluation revealed alloantibodies to red-cell antigens C, K, Kpa, Jsa, and S as well as anti-D and anti-e autoantibodies. After transfusion, both D-e+ and D+e-erythrocytes displayed markedly decreased in vivo 24-hour survival of 53 percent and 33 percent, respectively.
Patient 3
Patient 3 was a 32-year-old man with β-thalassemia intermedia. He had not received a transfusion since the age of five years because of his religious beliefs and those of his family. His hemoglobin level had been 7.0 to 8.0 g per deciliter until the age of 20, when it gradually began to decline. In the year before azacitidine therapy was begun, the level had fallen to 3.0 to 4.0 g per deciliter, and intermittent high-output cardiac failure developed.
Results
Patient 1
Figure 1AFigure 1
Response of Patient 1 to Treatment with Azacitidine. shows the clinical course of Patient 1. This patient no longer required transfusions after his first cycle of azacitidine at a daily dose of 2 mg per kilogram per day for four days. The patient tolerated six cycles of monthly treatment with azacitidine, and so a period of intense therapy began in which the cycles were repeated every two weeks. This allowed repeated phlebotomy with the removal of 2250 ml of blood over a period of 11 weeks. Despite the use of phlebotomy, the hemoglobin level continued to increase, reaching a maximal value of 11.6 g per deciliter. Unfortunately, because this schedule of treatment resulted in recurrent neutropenia (Figure 1B), the frequency of treatment was changed to every four weeks. Because the neutrophil count again began to decline, the daily dose of azacitidine was decreased to 1 mg per kilogram for the final nine cycles of treatment, during which the patient remained free of the need for transfusions.Figure 1C shows the patient's ferritin levels from 1985 through 1992. They were consistently higher than 2000 ng per milliliter despite the use of continuous chelation therapy. When azacitidine and phlebotomy were added to continued chelation, the ferritin level gradually fell below 600 ng per milliliter.
Figure 1D shows the patient's cardiac ejection fraction, as measured by radionuclide scanning, from 1983 to 1992. His base-line cardiac function and exercise response had both been consistently abnormal since first tested in 1983. In the several months before azacitidine therapy was begun, his ejection fraction was as low as 16 percent. After nearly two years of treatment with azacitidine, he had a nearly normal ejection fraction at rest and a normal exercise response for the first time. The goals of substantial iron unloading and improved cardiac function having been achieved, azacitidine was discontinued. At that time, the patient was not taking any cardiac medications, had an increased exercise tolerance, and was able to return to part-time employment.
Patient 2
The clinical course of Patient 2 is shown in Figure 2Figure 2
Response of Patient 2 to Treatment with Azacitidine.. As shown in Figure 2A, during the seven weeks before treatment with azacitidine, this 40-kg patient required 20 units of erythrocytes to keep her hemoglobin level above 5.0 g per deciliter. Her hemoglobin level had been as low as 3.2 g per deciliter. A trial of intravenous immune globulin given before azacitidine was begun did not increase her hemoglobin level, and neither did courses of prednisone and cyclosporine during treatment. After therapy with azacitidine was begun, the patient no longer required transfusions.This patient's long-term response to azacitidine is shown in Figure 2B. She was initially treated with a two-week cycle, which resulted in recurrent neutropenia. These episodes were eliminated and adequate hemoglobin levels were maintained when the cycle was lengthened to four weeks. At the most recent follow-up visit, the patient had a weakly positive direct antiglobulin test. She was able to resume full-time employment and returned to an active lifestyle.
Patient 3
The response of Patient 3 to treatment with azacitidine is shown in Figure 3Figure 3
Hemoglobin Levels and Reticulocyte Counts during Three Cycles of Azacitidine Therapy in Patient 3.. This patient had an increase in reticulocytes by day 5 of his first cycle of treatment. After two cycles of treatment, his hemoglobin level increased from 3.0 to 6.3 g per deciliter. However, for personal reasons, the patient withdrew from the protocol during his third cycle. He died three months later with a hemoglobin level of 1.4 g per deciliter.Hematologic Responses
The responses of the three patients to azacitidine are summarized in Table 1Table 1
Hematologic Responses of Three Patients with β-Thalassemia to Azacitidine.. Each patient had significantly increased average peak and trough hemoglobin levels. The fetal hemoglobin level increased in Patient 1. Pretreatment values for fetal hemoglobin were not available for comparison in Patient 2, because she had been receiving regular transfusions before therapy was begun. The mean corpuscular volume increased significantly in all patients, as did the mean corpuscular hemoglobin in Patients 1 and 2.Peak reticulocyte responses occurred between days 5 and 8 (Figure 3) (and data not shown). The absolute neutrophil counts reached a nadir most frequently between days 4 and 7 of the treatment cycles in Patient 1 and between days 2 and 6 in Patient 2 (data not shown). This pattern of neutropenia was not initially recognized because the counts exceeded 1000 per cubic millimeter at the start of the treatment cycles and when measured between cycles. The neutropenia lasted less than 1 week, except in the final 2-week cycle in Patient 1, during which it persisted for 12 days (data not shown).
Side Effects of Azacitidine
With any marrow-suppressive therapy there is a risk of infection. Patient 1 had an indwelling catheter that became infected three times, each time after a cycle during which his absolute neutrophil count fell below 1000 per cubic millimeter. Approximately two weeks after he received his last planned azacitidine treatment, cholangitic sepsis and aortic-valve endocarditis due to Pseudomonas aeruginosa developed. Patient 2 had a single episode of catheter-related infection and an apparent primary varicella-zoster infection that resolved without antiviral therapy. Neither episode was associated with neutropenia. Neither thrombocytopenia nor signs of increased extramedullary hematopoiesis were noted.
Discussion
We describe the use of a pharmacologic agent to alter the expression of a specific gene. This approach has produced long-term therapeutic benefit in two patients with end-stage β-thalassemia. The response of the patient with multiple erythrocyte antibodies (Patient 2) may have been due in part to an immunosuppressive effect of azacitidine, leading to a decrease in the autoimmune response to her erythrocytes. However, her direct antiglobulin test remained positive at follow-up. Although azacitidine was administered intravenously in this study, it has also been administered orally and intramuscularly, but with variable results9-11.
The only direct side effect of azacitidine was a dose-dependent neutropenia. We were able to compensate for this effect, while maintaining effective erythropoiesis, by reducing the size or frequency of the azacitidine doses. Our experience suggests that four-week treatment cycles in which a dose of 1 to 2 mg per kilogram per day is given for four days during each cycle should maintain adequate erythropoiesis, while lessening the tendency for neutropenia to develop.
Another risk of azacitidine is that it is a potential carcinogen. Although the drug has caused tumors in animal models, no associated human cancers have been reported in the literature. The absence of such reports may be related to the fact that azacitidine has primarily been used in the treatment of refractory acute myeloid leukemia and myelodysplastic syndromes20,21.
Given the potential risks associated with azacitidine therapy, it is clearly not appropriate for most patients with β-thalassemia. However, it may be beneficial in carefully selected patients for whom there are no other treatment options. Azacitidine may be particularly useful in patients with life-threatening iron overload. In these patients the use of limited periods of treatment to allow iron unloading should lessen the risk of side effects.
The long-term efficacy of azacitidine in patients with thalassemia highlights the potential usefulness of other agents that stimulate fetal globin synthesis22,23. We chose to use azacitidine in this study because it was the only agent with a demonstrated biologic effect in β-thalassemia. Since the initiation of this study, hydroxyurea has also been used to treat a series of patients with β-thalassemia. Although the base-line hemoglobin level increased from 4.0 to 5.0 g per deciliter to 6.0 to 7.0 g per deciliter in a single patient who did not require transfusions, in 11 other patients who were transfusion-dependent there was no decrease in the amount of transfused red cells required to keep the hemoglobin levels in the range of 8.0 to 9.0 g per deciliter24. Butyrate derivatives and erythropoietin are also being investigated as clinical stimulants of fetal globin synthesis25-27.
In this report, we describe a clinical regimen, designed to manipulate pharmacologically the expression of the fetal globin genes, that has produced long-term therapeutic benefit in two patients. This regimen not only appears to offer a new treatment option for patients with thalassemia, but also provides evidence that the pharmacologic manipulation of gene expression is a useful therapeutic strategy.
We are indebted to J. Kimbal, R.N., D. Vinning, R.N., L. Esposito, R.N., S. Moyer, and the nurses of the National Institutes of Health Clinical Center hematology ward for assisting in the care of these patients; to Drs. A. Shaw, P. Kamalaker, and R. Snihura for allowing us to share in the care of their patients; to Dr. G. Brittingham for liver iron measurements; and to Dr. K. McDonagh for helpful discussion.
Source Information
From the Section of Hematology and Oncology, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, N.H. (C.H.L.), and the Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. (A.W.N.).
Address reprint requests to Dr. Lowrey at the Section of Hematology and Oncology, Dartmouth-Hitchcock Medical Center, One Medical Center Dr., Lebanon, NH 03756.
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