Current Trends in the Management of Homozygous ß-Thalassemia

Transcription

1 Review Article Current Trends in the Management of Homozygous ß-Thalassemia From the Yale University School of Medicine, New Haven. Howard A. Pearson, MD Address reprint requests and correspondence to Dr. Pearson: Yale University School of Medicine, Department of Pediatrics, 333 Cedar Street, New Haven, CT 66510, USA. Accepted for publication 2 March Received 6 February HA. Pearson, Current Trends in the Management of Homozygous ß-Thalassemia. 1996; 16(5): ß-thalassemia is a genetic disease associated with decreased production of the ß-polypeptide chains of human hemoglobin. More than 100 different mutations have been identified that produce the thalassemia phenotype. Persons with the heterozygous state, thalassemia trait, have a mild microcytic anemia, with hemoglobin levels 1 to 2 g/dl below appropriate age and gender normal levels. Individuals with thalassemia trait usually have no symptoms. In contrast, homozygosity for thalassemia genes usually results in thalassemia major (TM) or Cooley's anemia, a severe, transfusion-dependent hemolytic anemia. The management of TM has undergone significant changes over the last two decades. This review will outline the management of these patients, the therapeutic considerations currently available and possible future interventions. The lifelong management of patients with TM involves several decision points and considerations: 1) The criteria for initiating transfusions. 2) The transfusion regimen: the blood product to be used, frequency of transfusions, and desired levels of hemoglobin to be maintained. 3) The criteria for performing splenectomy and the management of postsplenectomy complications. 4) The criteria for initiating chelation therapy with deferoxamine (DF) and the regimen to be used. 5) The periodic evaluation of DF therapy. 6) Results of modern transfusion and chelation therapy. 7) The status of oral iron chelating agents. 8) Prenatal diagnosis. 9) Bone marrow transplantation. 10) Pharmacological treatment. 11) The prospects for gene therapy. Criteria for Transfusions Almost all patients with TM require blood transfusion within the first two to three years of life to prevent severe anemia and its physical consequences. TM patients who are not transfused will only survive for a few years, although there is some variability in the age at which transfusions become necessary. 1 More than 70% of patients require transfusions by two years of age, and more than 90% require transfusions by five years of age. However, 5% to 10% of patients, who are usually designated as having "thalassemia intermedia" (TI), are able to maintain reasonable levels of hemoglobin (>70 g/l) without regular transfusions. Such TI patients usually have genetic mutations that result in less severe hematological disease. 2 A diagnosis of TM is made on the basis of a severe erythroblastic hemolytic anemia, typical RBC morphology, greatly elevated levels of Hb F, splenomegaly and marked expansion of the erythroid marrow that produces characteristic roentgenographic changes of the long bones and skull. 3 Both parents usually have ß-thalassemia trait, a mild hypochromic, microcytic anemia (MCV <78 f1) with elevated levels of Hb A 2 (>3.5%). An occasional microcytic parent will have normal levels of Hb A 2, but levels of Hb F >5.0% the so-called ß-δ thalassemia trait. Other parents may have a minor (5% to 10%) hemoglobin in the Hb S electrophoretic position called the Lepore hemoglobin. These trait variants are similar to the high A 2 thalassemia trait. 4 The newly diagnosed infant should be followed regularly. If the hemoglobin level falls consistently below 60 to 70 g/l, transfusions should be initiated. Even at these relatively high levels, if the child develops symptoms such as tachypnea, tachycardia, weakness, increased sleeping and growth failure, transfusions should also be begun. Some patients with TI may not require transfusions on the basis of their hemoglobin levels alone, but are begun on transfusions because of symptoms or because of progressive cosmetic changes of the face or bony changes resulting in pathologic fractures. The Transfusion Regimen Before transfusions are begun, RBC genotyping, which is as extensive as possible, should be done. After a child

2 begins receiving regular transfusions, it may be difficult to ascertain the RBC genotype. A small proportion of TM patients develop severe isoimmunization against multiple blood groups and even autoimmunization, which may make further transfusions difficult or even impossible. 5 If it has not been done previously, the patient should receive hepatitis B immunization. Transfusions should use packed or concentrated RBCs from which WBCs have been removed as completely as possible. This can be accomplished by using specific WBC filters, by washing the RBCs with large amounts of saline and centrifugation, or by the use of deglycerolized frozen RBCs. Removal of WBCs prevents the development of WBC antibodies and avoids febrile reactions, making transfusion premedication with antihistamines and hydrocortisone unnecessary. It is important to know the hematocrit of the RBC preparation that will be used. This information is necessary to determine the dose of RBCs to be administered with each transfusion and to estimate the survival of the transfused RBCs. The dose of RBCs to be given with each transfusion is based upon the hematocrit (HCT) of the RBC preparation, the frequency of transfusions and the child's weight. In general, a dose of 15 ml/kg of RBCs that have an HCT of 65% to 70% will raise the hemoglobin about 50 g/l. It is necessary to give approximately 20 ml/kg for the same increase if the RBCs have an HCT of 50% to 55%. These amounts of RBCs should require transfusion every four to five weeks to maintain a desired hemoglobin level. There are two philosophies concerning the lowest level of hemoglobin that should be maintained. The "hypertransfusion" regime attempts to keep the hemoglobin above 95 to 100 g/l. 6 The "supertransfusion" regimen attempts to keep the hemoglobin level above 120 g/l. 7 Because the supertransfusion regimen may require more frequent transfusions (every two to three weeks), most American centers are now employing "hypertransfusion." The hypothetical advantages of "supertransfusion," such as complete shut-off of erythropoiesis, greater reduction of GI iron absorption, and decreased blood volume, do not appear to have sufficient long-term benefits to balance the inconvenience and expense of more frequent transfusions. A number of studies have been done utilizing "neocyte" transfusions. Neocytes are prepared by centrifugation of blood to concentrate the younger, less dense RBCs. 8 Administration of young red cells with increased survival (neocytes) should theoretically reduce transfusion requirements. However, most studies have shown only a modest reduction which did not justify the increased expense and exposure to increased numbers of donors. 9 The Criteria for Splenectomy Most patients with homozygous ß-thalassemia require splenectomy at some time in their lives. In the past, before the use of hypertransfusion, the spleen often became massively enlarged in early infancy, and splenectomy was necessary to relieve the mechanical burden caused by its very large size. When splenectomy was done before six years of age, there was a high risk (10% to 20%) of severe postsplenectomy sepsis infection (PSI), which had a high rate of morbidity and mortality. 10 With the use of hypertransfusion, massive splenomegaly is unusual. Today the usual indication for splenectomy is evidence of increased destruction of transfused RBCs, which is indicated by an increased transfusion requirement. For example, a patient who has maintained a desired hemoglobin level (>100 g/l) with transfusions of 15 ml/kg of packed RBCs every four weeks is noted to require transfusions every two to three weeks to maintain this level. Annual transfusion requirements (ml of RBCs/kg/year) give an indication of RBC survival. If the RBCs have a normal survival, the annual blood utilization should be 175 to 200 ml RBCs/kg/year. Amounts in excess of 200 ml/kg/year indicate hypersplenism and are a reason to consider splenectomy. In almost every instance, it is possible to defer splenectomy until after six years of age, when the risk of PSI decreases greatly. 11 Following splenectomy, transfusion requirements are reduced considerably. Prior to elective splenectomy, immunization with pneumococcal and H. influenzae polysaccharide vaccines should be given. These patients regularly develop thrombocytosis after splenectomy. Thrombotic episodes have not been reported, even with platelet counts 1,000,000/mm 3 or even greater. Some centers advocate the use of low-dose salicylate therapy postsplenectomy, but there are no studies indicating that this is necessary. Because patients with asplenia have an increased risk of severe bacterial infections (PSI), prophylactic antibiotics are often advocated. Prophylactic penicillin (penicillin V, 125 mg to 250 mg p.o., b.i.d.) should always be given to children under five years of age. Prophylactic antibiotics in children over five years of age are probably not necessary. A study of children with the splenic dysfunction of sickle cell anemia showed a very low incidence of severe infection in children over five years of age and no significant difference between the incidence of severe infection in children receiving either penicillin or placebo. 12 However, asplenic patients and their families must understand that significant fever (>38.8 degrees C) may indicate a severe infection regardless of their age and whether prophylactic antibiotics are being used. Febrile, asplenic children must be examined immediately by a physician. A blood culture should be obtained and intravenous injection of a therapeutic dose of a broad spectrum

3 antibiotic should be given. The potential seriousness of fever in asplenic children must be reemphasized regularly. There are other unusual infections that occur in TM patients. A number of reports have described severe enterocolitis, caused by Yersinia enterocolitica, in TM patients. 13 Meningitis caused by Vibrio vulnificus has also been reported. 14 It is not clear whether these and other unusual infections occur because of asplenia or because of iron overload and the use of deferoxamine (DF). Criteria and Regimen for Chelation Therapy Patients receiving regular RBC transfusions inevitably develop iron overload. Transfusion of 200 ml of packed RBCs ultimately results in deposition of about 200 mg of iron into the tissues. Because there is no physiologic mechanism for iron excretion, repeated transfusions cause hemosiderosis, a pathologic accumulation of iron, especially in the liver, the endocrine organs and the heart. This results in organ dysfunction such as diabetes mellitus, congestive heart failure and cardiac arrhythmias. The average life expectancy of thalassemia patients is less than 20 years and survival beyond 30 years is unusual unless progressive hemosiderosis can be prevented. This unfavorable prognosis has been improved by iron chelation therapy, the administration of iron-chelating agents that combine with body iron and facilitate excretion in the urine and stool. The only iron-chelator currently available is deferoxamine (Desferal, DF). DF is an effecting chelating agent that is nearly specific for iron. Unfortunately, DF is not effective when given orally and so it must be administered parenterally, either subcutaneously (s.c.) or intravenously. Parenteral DF is rapidly cleared from the body and so must be injected repeatedly or administered over an extended period of time. Current DF protocols involve 10- to 12-hour s.c. or IV continuous injections of DF using small battery-driven infusion pumps. The subcutaneous route is generally used. The dose of DF is 30 to 40 mg/kg/day, diluted in 8 to 15 ml of distilled water. Patients are encouraged to use the DF pump five to six nights per week during sleep. DF-induced urinary iron excretion can be enhanced by the administration of 100 mg of ascorbic acid given on the days DF is used. Larger doses of ascorbic acid may produce iron toxicity in overloaded patients and should not be given. DF is remarkably safe. Auditory, visual and bony abnormalities have been described, but these have only occurred with DF doses in excess of 60 mg/kg/day. True allergy to DF has been rare, although many patients develop hard, painful lumps at the site of subcutaneous injections. These are probably due to needle position rather than allergy, because they do not occur every time DF is used and they cannot be prevented by the addition of hydrocortisone to the DF solution. Development of these painful lumps at subcutaneous injection sites is a frequent reason for poor compliance. DF is effective when administered intravenously, and use of permanent implanted intravenous catheters (Portocath) have been employed successfully. The major problem with DF therapy is patient noncompliance with the difficult, expensive and sometimes painful regimen, which must be given repetitively for an indefinite period of time. Compliance may also decrease because there is no immediate "positive feedback;" the patient notices no immediate symptoms when the medication is not used, even for long periods of time. The time to begin DF chelation therapy varies. DF is not effective until a significant excess of iron is present in the tissues. Further, DF toxicity is increased in patients who are not iron-overloaded to some degree. One accepted indication is to begin chelation therapy when the serum ferritin level is >1500 μg/l. Another indication is when the child has been on "hypertransfusion" for four to five years. A final indication utilizes a test dose of intramuscular DF with measurement of urinary iron excretion. 16 At the present time, there is no effective, safe oral iron chelating agent available. Studies with 1-2 dimethyl hydroxypyrid (L-1), an oral iron chelating agent, are currently being conducted in Europe and Canada. The drug is administered orally three to four times a day. L-l is not as effective as DF, and toxicity, especially by neutropenia, has been observed in a significant number of patients. 17 Evaluation of DF Chelation Therapy The child receiving DF therapy should be evaluated periodically. Height, weight, and Tanner staging should be measured. Bone age should be determined. Cardiac function should be assessed by echocardiography, including left ventricular ejection fraction. A 24-hour Holter monitor should be performed. Laboratory studies include serum ferritin, liver function tests, thyroid assessment, oral glucose tolerance test, and serum electrolytes, including Ca and PO 4. These tests can be modified or expanded, depending upon the patient's age. Results of Modern Transfusion and Chelation Therapy Morbidity and mortality of thalassemia major has been significantly improved by modern therapy. The severe

4 skeletal changes and the cosmetic abnormalities characteristic of thalassemia major in the past can be prevented. When chelation therapy is begun in early childhood and continued regularly, the complications of hemosiderosis can be prevented. There has been significant increase in life expectancy in children treated by these modern techniques. 18,19 In 1973, the average age of thalassemia patients in the US and Canada was 11 years. In 1993, the average age was 19 years. 20 Many patients are growing normally and undergoing age-appropriate puberty, events rarely seen 20 years ago. However, it must be noted that some patients who began chelation therapy after 10 years of age have not grown normally, have not had spontaneous puberty, and have evidence of hepatic, endocrine and cardiac damage. Because of a high rate of noncompliance with DF therapy, many patients continue to develop the complications of hemosiderosis. Prenatal Diagnosis Modern DNA technologies have precisely identified many specific thalassemia genes. This has permitted accurate prenatal diagnosis of thalassemia major. In at-risk pregnancies (both parents have thalassemia trait), prenatal diagnosis can be performed in the first trimester of pregnancy, using fetal DNA obtained by chorionic biopsy. The fetal genotype, homozygous or heterozygous thalassemia or normal, can be established, giving the parents the option of terminating severely affected pregnancies. Extensive carrier testing, combined with prenatal diagnosis, has been very successful in reducing the numbers of thalassemia major births in Greece, Italy and in the United States Bone Marrow Transplantation BMT offers the only cure available for thalassemia major. This has been extensively performed by Professor Lucarelli in Italy, who has done BMT in more than 400 patients with thalassemia major. 24 BMT has been performed much less frequently elsewhere in the world. In the US, only 32 BMTs for TM were reported through early Lucarelli's results indicate a 70% to 80% cure when good-risk thalassemia patients (young patients who do not have significant hepatic fibrosis) have an HLA- and MLC-compatible bone marrow transplant from a normal or thalassemia trait sibling. Some physicians and families, however, are unwilling to accept an immediate risk of death, which may be as high as 10% to 15%, as well as the possibility of graft rejection or graft-versus-host disease. There is little doubt that successful BMT is cost effective. The high, one-time cost of BMT is considerably less than the costs of chronic transfusions and DF chelation therapy. In parts of the world where availability of blood and DF is limited, BMT may be the treatment of choice if there is a histocompatible donor. BMT might also be indicated in patients who are chronically noncompliant with DF therapy. Pharmacological Therapy of Thalassemia Infants with homozygous TM are not anemic at birth, because they efficiently produce large amounts of fetal hemoglobin which contains γ, as opposed to ß, polypeptide chains. After birth, γ chains are produced in very small quantities because of the so-called γ-ß switch mechanism. The deficiency of γ chains and the lack of production of ß chains caused by homozygous thalassemia mutations result in a marked excess of α chains. Excess α chains precipitate in the RBCs, causing membrane damage and premature RBC destruction in the bone marrow (ineffective erythropoiesis). If it were possible to stimulate more effective γ-chain synthesis in later life, some of the abnormal pathophysiology of thalassemia major could be improved. A number of chemical agents can increase fetal hemoglobin synthesis in experimental animal studies, and a few of these have been studied in patients, including patients with TM and TI. These drugs include erythropoietin, cancer chemotherapeutic agents (hydroxyurea, HU, and 5-Aza cytidine), and most recently, derivatives of butyric acid. 26 The responses to these drugs in TM have been inconstant and, in general, disappointing. Short-term, continuous parenteral infusions of butyric acid derivatives have produced increases in hemoglobin levels in small numbers of patients. 27 However, the responses were not sustained. 28 The best results have been obtained in a few (four of 11) patients with TI who were treated with large doses of oral sodium phenylbutyrate. These patients showed increases of hemoglobin of 2 to 4 g/dl, which have been sustained for more than two years. 29 Studies are currently underway using combinations of these various drugs, but they currently appear to have limited clinical value. Gene Therapy The replacement of the abnormal thalassemia ß gene in RBC precursors with a normal ß gene could cure TM. Hemoglobinopathy gene therapy would require not only large amounts of ß-globin chain synthesis, but also complex

5 regulation of the balance between α and ß-chain production. An alternative strategy for gene therapy could involve the reactivation of γ chain synthesis by reversing the so-called γ-ß switch. However, gene therapy for TM appears to be in the distant future. Diseases whose control would require production of only small amounts of gene product, such as adenine deaminase-related immunodeficiency, are the current focus of most gene replacement research in humans. References 1. Silvestroni E, Bianco I. Screening for microcytosis in Italy. Am J Hum Gen 1975;27: Pearson HA. Thalassemia intermedia. Ann NY Acad Sci 1964;119: Caffey J. Cooley's anemia: a review of the roentgenographic findings. Am J Rad 1957;78: Pearson HA. Clinical aspects of the ß-thalassemias. In: Handin RI, Lux SE, Stossel TP, editors. Blood, Principles and Practice of Hematology. Philadelphia: Lippincott, 1995: Kruatrachue M, Sirisinha S, Pacharee P, et al. An association between thalassemia and autoimmune hemolytic anemia. Scand J Haematol 1980;25: Piomelli S, Karpatkin M, Arzanian M, et al. Hypertransfusion regimen in patients with Cooley's anemia. Ann NY Acad Sci 1974;232: Propper RD, Button LN, Nathan DG. New approaches to the transfusion management of thalassemia. Blood 1980;55: Corash L, Klein H, Deisseroth A, et al. Selective isolation of young erythrocytes for transfusion support of thalassemia major patients. Blood 1981;57: Cohen AR, Schmidt JM, Martin MB, et al. Clinical trial of young red cell transfusions. J Pediatr 1984;104: Smith CH, Erlandson ME, Stern G, et al. Postsplenectomy infection in Cooley's anemia. N Engl J Med 1962;266: Singer DB. Postsplenectomy sepsis. Perspect Ped Path 1973; 1: Falletta J, Wools GM, Veiter JI, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. J Pediatr 1995;127: Roche G, Leheup B, Gerard A, et al. Septicemia: a Yersinia enterolitica revue generate. Rev Med Intern 1982;3: Katz BZ. Vibrio vulnificus meningitis in a boy with thalassemia after eating raw oysters. Pediatrics 1988;82: Propper ED, Cooper B, Ruffo RR, et al. Continuous subcutaneous administration of desferrioxamine in patients with iron overload. N Engl J Med 1977;297: Smith RS. Iron excretion in thalassemia major after administration of chelating agents. Br Med J 1962;1: Olivieri NF, Koren G, Matsui D, et al. Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia. Blood 1992;79: Giardina PJ, Grady RW, Ehlers JM, et al. Chelation therapy in Cooley's anemia: a decade of experience with subcutaneous desferrioxamine in thalassemia major. Ann NY Acad Sci 1990;612: Olivieri NG, Nathan DG, MacMillan JH, et al. Survival of medically treated patients with homozygous ß-thalassemia. N Engl J Med 1994;331: Pearson HA, Cohen AR, Giardina PJ, et al. Survival and demography in thalassemia major. Pediatrics Alter BP. Antenatal diagnosis of thalassemia. Ann NY Acad Sci 1985;445: Cao A, Rossatelli C, Gallenello R, et al. The prevention of homozygous beta thalassemia by carrier screening and prenatal diagnosis in Sardinia. Clin Genet 1989;36: Pearson HA, Guiliotis DK, Rink L, et al. Patient age distribution in thalassemia major: changes between 1973 and Pediatrics 1987;80: Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in thalassemia. N Engl J Med 1990;322: Walters MC, Thomas ED. Bone marrow transplantation for thalassemia. The USA experience. Am J Ped Hem Onc 1994;16: Stamatoyannopoulos GA, Nienhuis AW. Therapeutic approaches to hemoglobin switching in treatment of the hemoglobinopathies. Ann Rev Med 1992;43:497.

6 27. Perrine SP, Gonder GD, Little J, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the ß globin disorders. N Engl J Med 1993:338: Sher GD, Gonder GD, Little J, et al. Extended therapy with intravenous arginine butyrate in patients with ß- hemoglobinopathies. N Engl J Med 1995,332: Dover DJ, Brusolow SW, Samid DV. Increased fetal hemoglobin in patients receiving sodium 4 phenylbutyrate. N Engl J Med 1995:337.