Approach Considerations
Management of Evans syndrome is challenging. Although almost all patients require therapy at some time during the course of the disease, the search for a consistent, effective, and nontoxic therapy continues. Medical therapy is the mainstay of management. Response to therapy varies even within the same individual, and the disease is characterized by periods of remission and exacerbation. No randomized trials have been conducted in patients with Evans syndrome, and the evidence for treatment is based on case reports, case series, and retrospective studies.
Patients admitted for severe anemia or thrombocytopenia should have respiratory and cardiovascular functions stabilized first; should receive blood product transfusions, if needed, after consultation with a pediatric hematologist; and should then be started on therapy with steroids or intravenous (IV) immune globulin (IVIg).
A study by Fan et al indicated that while glucocorticoid therapy is effective against AIHA, patients with Evans syndrome require longer treatment than do those with AIHA alone. [33]
In classic cases (ie, presenting with either autoimmune hemolytic anemia [AIHA] or immune thrombocytopenia), bone marrow aspiration is not indicated. When a patient has pancytopenia at presentation or when the diagnosis of immune thrombocytopenia is unconfirmed, bone marrow examination may help exclude an infiltrative pathology or an aplastic marrow. Bone marrow examination may be indicated in unusual cases, in cases refractory to treatment, or in cases when a peripheral blood smear suggests immature myeloid cells.
Additional therapies include splenectomy, administration of immunomodulatory agents, and hematopoietic stem cell transplantation. [34] Autologous and allogeneic stem cell transplantation have been used in a small number of patients (14 patients aged 5-52 years), with mixed results. [35]
Pharmacologic Therapy
Prednisone (eg, 1-2 mg/kg divided 2 or 3 times daily) is the most commonly used first-line agent and often effectively controls acute episodes of Evans syndrome. Although some patients are successfully weaned off steroids, relapses may occur in other individuals when prednisone is tapered or stopped. Accordingly, an alternate-day steroid regimen is advised, if feasible.
Patients with persistent immune cytopenia and those who require prolonged or high doses of steroids may benefit from IVIg (eg, 1-2 g/kg/day for 1-2 days. [36, 37] Thrombocytopenia is more responsive to this therapy than is hemolysis. Long-term control of thrombocytopenia is reportedly achieved with interval doses of IVIg.
Other therapies reported to be effective in small series include treatments with the following immunomodulating agents [28] :
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Alemtuzumab
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Danazol
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Cyclosporine [38]
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Azathioprine
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Cyclophosphamide
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Vincristine
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6-mercaptopurine
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Sirolimus
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Mycophenolate mofetil
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Bortezomib
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Rituximab
In one study, [28] where plasmapheresis was performed in 3 patients, 1 patient had transient responses, at best, to tacrolimus, protein A-Sepharose column plasmapheresis, whole-blood exchange transfusion, and total nodal irradiation. Another patient showed some response to treatment with a combination of Rh D immunoglobulin (anti-D), methotrexate, prednisone, and folic acid (responses to these agents varied).
Rituximab has shown varying results in refractory Evans syndrome. [39, 40, 41, 42, 43, 44, 45] At present, this agent seems to be used as a second-line therapy. Rituximab is approved for the treatment of relapsed and refractory B-cell non-Hodgkin lymphoma. Its binding to cells expressing CD20 results in cell death via a combination of mechanisms (eg, antibody-dependent cell cytotoxicity, complement activation, and apoptosis). Hence, it has been used to treat various autoimmune disorders mediated by autoantibodies.
Galor et al reported the successful use of rituximab in a patient with Evans syndrome. [39] Mantadakis et al reported the successful use of this agent in a patient with long-lasting Evans syndrome refractory to standard treatments; the patient responded well to rituximab and then responded again when relapse occurred 7 months later. [40] In contrast, Grossi et al treated 2 patients with rituximab without success. [46] In fact, the patients had a worsening of their anemia.
Zecca et al described the weekly use of rituximab in 5 children with Evans syndrome, all of whom were successfully treated. [41] In a retrospective review of patients at the Mayo Clinic, Shanafelt reported responses in one, but not both, of the cytopenias among 3 patients with Evans syndrome. [42]
A review by Norton and Roberts of the use of rituximab in 18 patients (age, 0.3-65 years) yielded encouraging results, with sustained complete remission lasting as long as 17 months. [47] In a pediatric prospective series by Rao et al, 2 patients with Evans syndrome were treated with rituximab; 1 had a partial response, and 1 had no response. [44] Complications associated with rituximab in these studies have been minimal; the most common is infusion-associated reaction.
A prospective study by Ducassou et al reported that in children treated with rituximab, those with isolated AIHA responded better than did those with AIHA associated with Evans syndrome. The rate of complete response to rituximab was 74% in children with isolated AIHA, compared with 40% in those with Evans syndrome, while the rates of 6-year relapse-free survival were 53% and 36%, respectively. [48]
Another agent that has been tried is alemtuzumab, a humanized immunoglobulin G (IgG) monoclonal antibody specific for the CD52 antigen present on T cells and B cells. Willis et al reported on the use of alemtuzumab in 3 patients with Evans syndrome; though a response was seen in 2 patients, both experienced relapses within 3 months. [49]
One pilot study showed that a multiagent approach may be effective in patients with Evans syndrome. [50] Transfusions of red blood cells (RBCs) and platelets were also used as adjuncts to treatment.
In a multicenter study of 156 children with Evans syndrome, Aladjidi et al found that at least one second-line immune treatment (eg, azathioprine, anti-D, cyclosporine, colchicine, hydroxychloroquine, mycophenolate mofetil, rituximab, thrombopoietin-receptor agonists, splenectomy) was needed in 108 cases (69%). [51]
Splenectomy
Splenectomy does not have a clearly established role in the treatment of Evans syndrome, but it may be considered in refractory cases. Splenectomy may improve the CBC and reduce steroid dependence; however, relapses are common and, in most cases, occur within 1-2 months after the procedure.
According to a national survey, splenectomy provided a reported duration of response that ranged from 1 week to 5 years; however, the median response duration was just 1 month. [28] A retrospective study by Sulpizio et al indicated that the 1-year remission rate following splenectomy is greater in patients with immune thrombocytopenia than in those with Evans syndrome. The investigators reported that the initial and 1-year response rates after splenectomy were 85.7% and 42.8%, respectively, in patients with Evans syndrome, compared with 90.9% and 70.1% in the immune thrombocytopenia cohort. Thus, the study found the 1-year postsplenectomy relapse rate in Evans syndrome to be 42.8%. [52]
The risk of postsplenectomy sepsis appears to be increased in children with Evans syndrome, especially those with pancytopenia. Prior to splenectomy, all patients should be immunized against S pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. Additionally, postsplenectomy antibiotic prophylaxis may be indicated, potentially for the patient's lifetime.
Diet and Activity
Dietary restrictions are not usually required. Patients receiving steroid therapy should have some restrictions placed on their salt, sugar, and fluid intake to prevent excessive fluid retention.
Activities may have to be restricted depending on symptoms, the age of the patient, and the degree of thrombocytopenia and anemia.
Consultations
The following consultations may be considered as appropriate:
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Pediatric hematologist
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Pediatric oncologist
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Rheumatologist
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Immunologist
Long-Term Monitoring
A patient may be discharged if he or she is clinically stable (eg, if blood counts are rising). Weekly follow-up is recommended with blood counts and physical examinations until counts become stable or return to reference ranges. Subsequent follow-up care may be arranged at intervals of 2-4 weeks. More frequent follow-up care may be indicated for patients with clinical or laboratory signs of recurrence (eg, when steroids are tapered).
