Thalassemia Intermedia Treatment & Management
- Author: Hassan M Yaish, MD; Chief Editor: Robert J Arceci, MD, PhD more...
The diagnosis of thalassemia intermedia is purely clinical and is usually made after a period of observation to determine that the patient is able to maintain a satisfactory hemoglobin (Hb) level for a long time without the need for blood transfusions. If the physician settles for a marginal level of Hb and decides not to initiate blood transfusion therapy, the patient's Hb level may fluctuate and decrease further, potentially reaching a very low level if the patient is not closely monitored. Should this occur, permanent damage, including heart failure, bone deformity, hypersplenism, liver damage, or other complications, may occur. In otherwise similar circumstances, patients with marginally severe disease should be treated in the same way as patients with thalassemia major.
Most medical care in thalassemia intermedia is provided in an outpatient setting. Inpatient care is reserved for surgical procedures such as splenectomy or resection of large extramedullary hematopoietic tumorlike masses compressing vital organs, infectious complications, or in rare severe cases that are treated by a bone marrow transplant.
Patients in whom thalassemia is suspected should be seen and evaluated by a hematologist. In addition, consultation with the following specialists is recommended:
Cardiologist: For evaluation of cardiac function and monitoring of potential complications due to the anemia, transfusion, or iron overload
Endocrinologist: For evaluation of possible involvement of various endocrine glands, which could result in diabetes mellitus, thyroid disorder, or growth retardation
Gastroenterologist: For diagnosis and management of liver complications.
Many patients with thalassemia intermedia should be able to tolerate most daily activities. However, once the anemia worsens, exercise intolerance develops and may represent a warning sign indicating the need for initiation of blood transfusions. Massive splenomegaly has been observed in severe cases and is a cause for limiting the patient's activity for fear of injury to the abdomen causing rupture of the spleen. Regular transfusions decrease the size of the spleen in most instances, allowing splenectomy to be avoided whenever possible.
The treatment of most cases of thalassemia intermedia involves close monitoring and observation. Patients with satisfactory hemoglobin (Hb) levels are frequently monitored. These patients usually require blood transfusions only on certain occasions such as the presence of intercurrent infections, hypersplenism, or other illnesses.
If patients can no longer maintain an Hb level of more than 6 g/dL, they are either started on a regimen of regular blood transfusions or a different option, such as splenectomy, should be tried. Patients with evidence of hypersplenism have a good chance to have their need for blood transfusion reduced or totally eliminated; this might last for months or years.
Administration of one of the drugs that may induce stress erythropoiesis and raise Hb levels may be tried. Hydroxyurea has been frequently used for this purpose. In separate studies on a large number of patients, a response rate exceeding 75% was reported after long-term therapy. However, this high rate of response was not confirmed by other studies until a study on a small number of patients with β thalassemia major and intermedia treated with hydroxyurea demonstrated a response rate of more than 82%.
Marrow suppression and cytopenia could be a real concern in patients receiving hydroxyurea. In searching for new agents without such adverse effects, pomalidomide was found to augment fetal hemoglobin production in mice without the myelosuppression effect of hydroxyurea. Further evaluation of this agent for possible clinical application is warranted.
Many studies have shown that patients with thalassemia intermedia who are not on regular blood transfusion because of their milder symptoms nevertheless develop major complications related to their chronic anemia and ineffective erythropoiesis (IE). Considering the cost-benefit balance of regular treatment in patients with thalassemia major, most patients with thalassemia intermedia would apparently benefit from similar therapy to prevent the complications, rather than waiting to deal with such complications when they occur.
The initial regimen includes transfusion of 10-15 mL of packed red blood cells (PRBCs) every 4-5 weeks to keep the Hb level over 10 g/dL. Blood transfusions should be leukocyte poor to avoid sensitization, because such patients have the potential of becoming transfusion dependent in the future. Patients should be checked and typed for minor blood groups to avoid further difficulties in providing appropriate blood for them in the future. Identification of a small group of dedicated donors minimizes the risk of viral exposure and alloimmunization. (See also Transfusion and Autotransfusion, Transfusion-Induced Iron Overload, Alloimmunization From Transfusions, and Transfusion Reactions.)
Iron status must be carefully monitored, and patients with iron overload should be treated with an aggressive chelation regimen as soon as indicated. A previously popular chelation regimen includes administration of deferoxamine 5 days per week as a subcutaneous (SC) infusion over 8-12 hours. This regimen had revolutionized the treatment of β thalassemia major in patients regularly receiving PRBC transfusions and resulted in longer survival and near-normal quality of life.
An oral iron chelator, deferasirox (Exjade), has been in use in the United States for some time. This agent has a long half-life and, for this reason, is orally (PO) administered once daily. Several studies have confirmed the long-term efficacy and safety of this agent. It is now much more popular relative to deferoxamine and, due to the ease and convenience of administration and better compliance, is probably replacing deferoxamine.
A similar dose is often administered at the time of blood transfusions to help bind the transfused iron (from hemolyzed RBCs).
A 5-year prospective European study reported on 555 children and adults who were divided into 2 groups, the first treated with deferasirox for a total of 5 years (deferasirox cohort) and the second started on deferoxamine for the first year then switched to deferasirox (cross-over cohort). At the end of the treatment period, a liver biopsy was obtained and HIC was measured in the 2 groups and compared with the initial level before treatment. In the deferasirox cohort, HIC decreased by 7.8 ±11.2 mg Fe/g dry weight. In the cross-over cohort, the decrease was somewhat less, at 3.1 ±7.9 mg Fe/g dry weight.
These findings support the long-term efficacy of this oral chelating agent, which also was proven to be safe with only minimal adverse effects reported, including increased blood creatinine in 11.2%, abdominal pain in 9%, and nausea in 7.4%. No adverse effects on growth in children or sexual development in adolescents were noted.
In January 2013, the FDA approved deferasirox (Exjade) for treatment of chronic iron overload caused by nontransfusion-dependent thalassemia. Deferasirox is a selective trivalent iron chelator that reduces liver iron concentration (LIC) and serum ferritin levels. Approval was based on two clinical trials that measured the number of patients whose LIC was reduced to < 5 mg/g dry weight after 52 weeks of treatment. In the first trial, 166 patients received 5 mg/kg or 10 mg/kg of deferasirox, or a placebo daily. Results showed 15% and 27% of deferasirox-treated patients, respectively, achieved the target LIC compared with 4% of placebo-treated patients. The second trial included 133 patients from the first study who received an additional year of deferasirox treatment or switched from placebo. Of the evaluable patients in this group, 35% achieved the target LIC.
Correction of nutritional deficiencies
Nutritional deficiencies should be addressed and treated. A well-balanced diet with adequate folic acid supply is a necessity, and a folic acid supplement should be administered in those with folic acid deficiency. Foods with high iron content should be avoided, particularly meat, because heme iron is especially well absorbed. Vitamin C supplementation has been effective in enhancing the efficiency of chelating iron from tissues and assists absorption of dietary iron; therefore, patients should avoid co-ingesting vitamin C and iron-rich foods. Alternatively, drinking tea with iron-rich foods helps chelate some of the iron before it is absorbed in the bowels.
Antibiotic and vaccine prophylaxis
Appropriate vaccinations, including the polyvalent polysaccharide pneumococcal, the Haemophilus influenzae type b, and the quadrivalent meningococcal vaccines, should be administered to patients 1-2 weeks before splenectomy. Patients who have undergone a splenectomy should be placed on prophylactic antibiotics and be treated empirically for any signs of infection or fever while awaiting the results of blood cultures.
Patients with severe β thalassemia intermedia are prone to infection with Yersinia enterocolitica, similar to individuals with the severe forms of thalassemia major. For this reason, patients who develop fever without clear cause should receive appropriate treatment even if culture results are negative.
See the Medications section for more information on antimicrobial agents and vaccines.
Bone marrow transplantation
In patients with severe thalassemia intermedia who require aggressive therapy to sustain life, bone marrow transplantation, similar to that performed in patients with thalassemia major, is a reasonable alternative to transfusion and chelation if a matched sibling donor is available.
Placement of a central vascular access catheter in patients with severe disease is very helpful for blood transfusions, and laboratory work, especially when accessing a patient's peripheral veins becomes very difficult.
Splenectomy is frequently recommended for patients with thalassemia intermedia who are no longer able to maintain an adequate hemoglobin (Hb) level. It is usually performed to restore the Hb steady state in patients who are not receiving blood transfusions and frequently succeeds in averting the need for regular transfusions.
Observations and case reports have shown that splenectomy in such patients may cause serious venous thrombotic events, ranging from deep vein thrombosis (DVT) to pulmonary thrombotic lesions complicated by pulmonary hypertension.[14, 36, 37, 38] Owing to several reports of serious thrombotic events such as transient ischemic attacks (TIAs) associated with hemiparesis and intracranial manifestations of Moyamoya syndrome were reported postsplenectomy in patients with thalassemia intermedia, one should delay or reconsider such a procedure whenever possible. This is supported by the fact that many children who underwent splenectomy to avoid becoming transfusion dependent experienced only a transient effect, and most required regular transfusions later.
Even though a good response to splenectomy is frequently encountered, it is occasionally unpredictable and could even be harmful. In a report, 2 transfusion-naïve siblings with thalassemia minor clinical conditions had deteriorated, becoming transfusion dependant shortly after they underwent splenectomy for enlarged spleens. One of the siblings also developed thrombotic events post splenectomy. The patients were found to have co-inherited a β+ thalassemia mutation together with a complete duplication of the α globin gene cluster on both alleles.
In the rare patient with large tumorlike masses that compress vital organs, surgical resection rather than radiation therapy is usually preferred.
Most complications expected in thalassemia intermedia have been described previously. The conversion of thalassemia intermedia to a transfusion-dependent state is, by itself ,the most serious complication, because that marks the transition of thalassemia intermedia to a more severe form of β thalassemia.
As a result of the advanced care provided to patients with thalassemia, they are now surviving to an advanced age. With this longer survival comes new problems, which require a change in the approach to the care of affected patients. Three such complications recently been described as major issues in the adults with thalassemia: hepatitis C virus (HCV) infection, thrombotic events, and fertility issues.
HCV infection is a major complication of the lifelong blood transfusions in patients with the severe forms of thalassemia. This is probably less of a problem in patients with thalassemia intermedia who are not transfusion dependent. Nevertheless, HCV has also been reported in patients with thalassemia who have never had transfusions.
The incidence of positive HCV antibodies or RNA in patients aged 25 years or older (who were treated before the screening for HCV was initiated in 1990) was reported by the Thalassemia Clinical Research Network (TCRN) to be as high as 70% compared with only 5% in patients aged 15 years or younger. The American Association of Blood Banks (AABB) has reported that the chance to contract HCV from blood transfusions in the United States is 1 per 1 million units transfused. Unfortunately, this is not the case in some developing countries where the rate was reported to be 63.8%.
HCV and iron overload are risk factors for cirrhosis and hepatocellular carcinoma (HCC); for this reason, many authors recommend monitoring such patients closely with liver ultrasonography and alpha fetoprotein level (AFP) levels. About 33% of patients with HCV in North America are expected to spontaneously clear the virus; if this does not occur, aggressive treatment should be initiated. Pegylated interferon alpha (INF-alpha), in combination with ribavirin, has been very effective in treating children with HCV infection.
Thrombotic events have been increasingly encountered not only in patients with thalassemia intermedia but also in those with thalassemia major and β thalassemia/Hb E disease. In one study of 85 patients with thalassemia intermedia and 65 with thalassemia major, the incidence of venous thromboembolic events was 29% and 2%, respectively ; 23 of the 24 patients with thalassemia intermedia and venous thromboembolic events had undergone splenectomy. For this reason, some recommend short-term antithrombotic therapy both perioperatively and when a risk factor for thrombosis exists. A low-dose daily aspirin is also recommended for all patients with thalassemia who are splenectomized and for those with thalassemia major and a platelet count of 600,000/μL after splenectomy.
The leading cause of morbidity and mortality in thalassemia major patients is cardiac siderosis. This is not the case in thalassemia intermedia patients, however, since pulmonary hypertension and thrombosis are the major forms of cardiovascular complications in this condition. Endothelial dysfunction in thalassemia intermedia is thought to play a major role in causing thrombotic events.
It has been suggested that patients with thalassemia intermedia exhibit a proatherogenic biochemical phenotype, which may contribute to the cardiovascular risk in thalassemia intermedia patients. The serum Fe level and Fe saturation were significantly higher in thalassemia intermedia than in both thalassemia major and normal controls. The hepcidin level, as well as the transferrin level, were also lower in thalassemia intermedia than in the thalassemia major and controls. Thalassemia intermedia patients also exhibit lower high-density lipoprotein and increased cytoplasmic neutral lipid values.
Fertility in adult patients with thalassemia is another new issue that providers have to deal with. Other complications that can arise include the following:
Hypersplenism: Severe thalassemia is often characterized by hypersplenism, which usually results in exaggerated anemia, thrombocytopenia, and enlarged abdomen
Iron overload, liver disease, and cardiac and endocrine defects are also encountered in this condition
Bone deformities, fractures, and neurologic complications from compression by tumorlike extramedullary hematopoietic tissue masses are more frequently observed in thalassemia intermedia than in thalassemia major, because the hyperactivity of the marrow in patients with untreated thalassemia intermedia is not suppressed by repeated blood transfusions
Complications of blood transfusions, such as hepatitis and other transmitted organisms, are all well known
Frequent outpatient visits are needed in the early stages of thalassemia intermedia to monitor the patient's hematologic parameters, activity, exercise tolerance, growth, and development of bone changes.
Once the patient requires regular transfusions, monthly outpatient visits for blood transfusions and laboratory work for monitoring iron load status are usually required. Guidelines for transfusion in neonates and older children have been established.
While receiving chelation therapy, patients should have eye examinations and hearing tests as part of monitoring for the complications of therapy.
Young children should have their growth and development closely monitored; any deviation from normal should alert the physician to further investigate the need for blood transfusions. Failure to thrive, exercise intolerance, bone deformities and fractures are all potential complications; the healthcare provider should always look for ways to prevent these complications or at least identify and treat them early with regular blood transfusions, which are frequently effective in reversing or preventing their progress.
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