Evans Syndrome

Evans Syndrome – Introduction

Rare autoimmune disorder, usually occurs in children (but can occur in adults), characterized by simultaneous or sequential development of autoimmune hemolytic anemia and immune thrombocytopenia with or without immune neutropenia^(1,3)
May be primary (idiopathic) or secondary (associated with an underlying disease)⁽¹⁾

Definitions

Definition of Evans syndrome differs in the literature; definitions include⁽⁴⁾
- autoimmune disease involving ≥ 2 lineages
- autoimmune cytopenia involving red blood cells and platelets, with or without neutrophil destruction
- clinically relevant cytopenia of multiple lineages
- immune thrombocytopenia with positive direct antiglobulin test results with or without sign of hemolysis

Types

Evans syndrome can be categorized into primary (idiopathic) or secondary (associated with underlying disease)⁽¹⁾
- in a cohort of 156 children (median age 5.4 years) with Evans syndrome from France
  - primary disease in 30%
  - secondary with
    - various unclassified immune manifestations in 60%
    - other underlying disease (mainly genetically identified immunodeficiency or systemic lupus erythematosus (SLE)) in 10%
  - Reference – Front Pediatr 2015 Sep 29;3:79 full-text
- in cohort of 68 adults (mean age 55 years) with Evans syndrome from France and Italy, Evans syndrome was idiopathic in 34 patients (50%) and secondary in 34 patients (50%) (Blood 2009 Oct 8;114(15):3167 full-text)
underlying conditions contributing to secondary Evans syndrome in children may include⁽¹⁾
- infections such as
  - Epstein-Barr virus
  - cytomegalovirus
  - HIV
  - hepatitis C
  - Mycoplasma pneumoniae
  - parvovirus B19
- immunodeficiency and lymphoproliferative disorders such as
  - common variable immunodeficiency (CVID)
  - severe combined immunodeficiency (SCID)
  - DiGeorge syndrome
  - selective IgA deficiency
  - lipopolysaccharide-responsive and beige-like anchor deficiency
  - cytotoxic T-Lymphocyte Antigen-4 deficiency
  - phosphoinositide 3-kinase delta mutations
  - Castleman disease
  - autoimmune lymphoproliferative syndrome (ALPS)
    - in cohort of 45 children with Evans syndrome, 47% had ALPS (Blood 2010 Mar 18;115(11):2142 full-text)
    - in cohort of 23 children previously diagnosed with Evans syndrome (mean age at presentation 5.9 years) 7 children had ALPS-like syndrome and 6 children had other primary immunodeficiencies (Pediatr Blood Cancer 2016 Feb;63(2):292)
  - tripeptidyl-peptidase II deficiency – Evans syndrome reported in 2 sibling children (age of presentation 21 months and 18 months) with tripeptidyl-peptidase II deficiency in case series (Blood 2015 Jan 29;125(5):753 full-text)
- autoimmune and rheumatologic disorders such as
  - systemic lupus erythematosus (SLE)
  - antiphospholipid syndrome
  - rheumatoid arthritis (RA)
  - giant-cell hepatitis
  - in cohort of 23 children with previously diagnosed Evans syndrome (mean age at presentation 5.9 years) 1 child had SLE and 6 children had other types of autoimmunity (Pediatr Blood Cancer 2016 Feb;63(2):292)
- malignancy such as
  - lymphoma
  - leukemia
  - myelodysplasia
- exposure to
  - drugs
  - vaccination
  - post stem cell transplantation
underlying conditions contributing to secondary Evans syndrome in adults
- in cohort of 34 adults from France and Italy with secondary cases of Evans syndrome, underlying conditions included
  - autoimmune diseases including SLE, “incomplete” lupus, primary antiphospholipid syndrome, or Sjogren syndrome in 14 patients
  - immunodeficiencies including CVID, or immunoglobulin A (IgA) deficiency in 6 patients
  - lymphomas including B-cell Non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, or T cell non-Hodgkin lymphoma in 6 patients
  - chronic myelomonocytic leukemia in 1 patient
  - monoclonal gammopathy of undetermined significance in 1 patient
  - hepatitis C in 1 patient
  - congenital asplenia in 1 patient
  - idiopathic CD4 lymphocytopenia in 1 patient
  - other unclassified lymphoproliferative disorder in 3 patients
  - Reference – Blood 2009 Oct 8;114(15):3167 full-text
- Evans syndrome diagnosed in 39-year-old woman with paraneoplastic syndrome in case report (pulmonary papillary carcinoma) (Thorac Cancer 2017 Jan;8(1):57 full-text)

Epidemiology

Who is Most Affected

can occur in both children and adults⁽³⁾
- in a cohort of 156 children from France with Evans syndrome, median age 5.4 years at onset of cytopenia (Front Pediatr 2015 Sep 29;3:79 full-text)
- in a cohort of 68 adults (60% female, mean age 55 years) from France and Italy with Evans syndrome, mean age 52 years at diagnosis of immune thrombocytopenia and autoimmune hemolytic anemia (Blood 2009 Oct 8;114(15):3167 full-text)
diagnosis of Evans syndrome reported in 0.8%-3.7% of all patients with either immune thrombocytopenia (ITP) (in adults or children) or autoimmune hemolytic anemia (AIHA) at onset (Blood 2009 Oct 8;114(15):3167 full-text)
in patients with AIHA, multilineage involvement reported in 13%-73%⁽¹⁾
- in a cohort of 35 children (median age 10 years) from the United States with AIHA, 7 (20%) presented with Evans syndrome (J Pediatr Hematol Oncol 2016 Apr;38(3):e120)
- in a cohort of 265 children (median age 3.8 years) from France with AIHA, Evans syndrome was diagnosed in 99 (37%) (Haematologica 2011 May;96(5):655 full-text), commentary can be found in Haematologica 2011 Nov;96(11):e43
- in a cohort of 308 adults from Italy with primary AIHA, 21 (7%) were diagnosed with Evans syndrome (Blood 2014 Nov 6;124(19):2930 full-text)
in a cohort of approximately 500 adults with ITP, Evans syndrome diagnosed in about 5% (Blood 2009 Oct 8;114(15):3167 full-text)

Incidence/Prevalence

rare^(1,3)
- incidence of autoimmune hemolytic anemia in children 0.4 cases per 100,000 children per year; multilineage involvement reported in 13%-73% of cases
- approximately 10 new pediatric cases diagnosed per year in France (Front Pediatr 2015 Sep 29;3:79 full-text)

Etiology and Pathogenesis

Causes

autoantibody directed against red blood cell self-antigens; autoantibody may be either⁽¹⁾
- immunoglobulin (Ig) G with maximal reactivity at 37 degrees C (98.6 degrees F)
- IgM with maximal reactivity typically at 0 degrees C (32 degrees F)

Pathogenesis

mechanisms of immune-mediated hemolysis vary and include⁽¹⁾
- autoreactive immunoglobulin (Ig) G antibodies that bind to red blood cell (RBC) antigens, with maximal activity typically at 37 degrees C (98.6 degrees F)
- autoreactive IgM antibodies that bind to RBC antigens, with maximal activity typically at 0 degrees C (32 degrees F)
- both autoreactive antibodies may coexist
immune thrombocytopenia is mediated by platelet opsonization with antiplatelet antibodies and/or immune-complexes⁽¹⁾
immune-mediated destruction of neutrophils is caused by antibodies that recognize membrane antigens, especially those located on IgG fragment crystallizable receptor type 3b (Fc gamma IIIb receptor)⁽¹⁾
cytopenia in children with autoimmune lymphoproliferative syndrome⁽¹⁾
- may be caused by a defect of apoptosis stimulating fragment apoptotic pathway, leading to increased lymphocyte survival, lymphoproliferation, and autoimmunity
- Evans syndrome associated with decreased CD4/CD8 ratio and increased production of interleukin -10 and interferon gamma

History and Physical

Clinical Presentation

in children⁽¹⁾
- severity of the disease varies from mild to life-threatening
- disease is often relapsing/resistant to treatment or chronic
autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) reported to develop concomitantly or separately after median interval of 3 years⁽¹⁾
- in a cohort of 156 children from France with Evans syndrome
  - AIHA preceded onset of ITP in 39 patients (25%)
  - ITP preceded onset of AIHA in 46 patients (29%)
  - simultaneous AIHA and ITP in 71 patients (46%); mean delay between cytopenias 2.4 years
  - autoimmune neutropenia observed in 32 patients (20%); neutropenia observed prior to diagnosis of Evans syndrome in 2 patients, after diagnosis in 30 patients
  - Reference – Front Pediatr 2015 Sep 29;3:79 full-text
- in cohort of 68 adults from France and Italy with Evans syndrome
  - AIHA preceded onset of ITP in 11 patients (16%)
  - ITP preceded onset of AIHA in 20 patients (29.5%)
  - simultaneous AIHA and ITP in 37 patients (54.5%); mean delay between cytopenias 4.2 years
  - autoimmune neutropenia observed in 10 patients (14.7%)
  - Reference – Blood 2009 Oct 8;114(15):3167 full-text
patients may present with symptoms of⁽¹⁾
- anemia such as
  - pallor
  - jaundice
  - fatigue
  - dyspnea
  - hematuria/hemoglobinuria
- thrombocytopenia such as
  - petechiae
  - bruising
  - mucocutaneous bleeding
- neutropenia including infection-related symptoms
patients may also present with lymphadenopathy and hepatosplenomegaly⁽¹⁾

History

ask about⁽¹⁾
- patient and family history of
  - malignancies
  - infections
  - immunological disorders
- recent exposure to drugs or vaccinations that might trigger cytopenia

Physical

General Physical

patients commonly present with fever⁽¹⁾
examine for lymphadenopathy⁽¹⁾

Skin

look for⁽¹⁾
- pallor
- jaundice
- petechiae
- bruising
- mucocutaneous bleeding

Cardiac

assess patient for⁽¹⁾
- tachycardia
- murmur (due to the anemia)
- S3 gallup

Abdomen

examine for hepatosplenomegaly⁽¹⁾

Diagnosis

Making the Diagnosis

clinicopathological diagnosis based on demonstrating hemolytic anemia, serological evidence of anti-red blood cell autoantibodies by direct antiglobulin test (DAT) , and thrombocytopenia^(1,2)
about 50% of patients present with both autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) simultaneously and about 25% with just AIHA; thus, majority of patients will have symptoms of hemolytic anemia with positive direct antiglobulin test (DAT) at diagnosis
about 25% of patients will present with ITP and will not present with symptoms of anemia
patients with neutropenia who develop AIHA or ITP are considered to have Evans syndrome⁽⁴⁾
patients with Evans syndrome^(1,2)
- typically have anemia with elevated reticulocytes and may have increased mean corpuscular volume (Med Clin North Am 2017 Mar;101(2):351)
- will have indications of hemolysis
  - detected in blood tests including
    - increased bilirubin (unconjugated)
    - increased lactate dehydrogenase
    - decreased haptoglobin
  - presence of urinary hemosiderin (may be detected about 1 week after intravascular hemolysis)
- may have thrombocytopenia and/or neutropenia
- peripheral blood smear may show spherocytes
- DAT result is usually positive for
  - immunoglobulin (Ig) G or IgG and complement if warm AIHA
  - complement if cold AIHA

Differential Diagnosis

conditions that may result in anemia such as⁽¹⁾
- nonimmune red blood cell (RBC) membrane disorders
- RBC enzyme deficiency
- hemoglobinopathies
- Wilson disease
- paroxysmal nocturnal hemoglobinuria (PNH)
conditions that may result in thrombocytopenia such as⁽¹⁾
- acquired thrombotic thrombocytopenic purpura
- inherited ADAMTS13 deficiency
- hemolytic-uremic syndrome (HUS)
- Kasabach-Merritt syndrome, hemangioma with thrombocytopenia, and other causes of localized intravascular coagulation
- disseminated intravascular coagulation (DIC)
- monoclonal lymphoproliferation

Testing Overview

initial blood tests for anemia and hemolysis should include^(1,2)
- complete blood count and reticulocyte count
- peripheral blood smear
- lactate dehydrogenase level
- haptoglobin level
- indirect (unconjugated) bilirubin level
urine testing includes⁽²⁾
- dipstick and microscopy
- hemosiderin
testing to confirm immune-mediated mechanism of hemolysis includes
- direct antiglobulin test (DAT)
  - to determine type of autoimmune hemolytic anemia (AIHA), at minimum, perform DAT using monospecific anti-immunoglobulin (Ig) G and anti-C3d (BCSH Grade 1C); however, polyspecific antihuman globulin (AHG) may be used for the initial DAT, but if DAT is positive, monospecific AHG should be used to determine if IgG or complement is present
  - screen patients for presence of cold antibodies if DAT positive for complement and/or IgG by repeating DAT at room temperature (BCSH Grade 1C) or by other methods approved by individual institutions
- in rare cases, patients with AIHA may have DAT-negative AIHA due to low affinity and low levels of antibody or red blood cells (RBCs) bound by Ig that is not tested for in the standard DAT (for example, IgA or IgM); in these cases, additional testing may be indicated such as
  - RBC eluate testing
  - column agglutination DAT using monospecific anti-IgG and anti-complement or anti-IgA if available
  - use of other DAT detection methods such as flow cytometry, enzyme-linked immunosorbent assay, microcolumn agglutination test, solid-phase agglutination test, and mitogen-stimulated-DAT (usually performed at a reference laboratory)
tests to identify underlying conditions contributing to Evans syndrome
- for all children
  - consider testing for other immunological diseases (BCSH Grade 1A)
  - consider liver function tests (BCSH Grade 2C)
- other tests may include screening for
  - infections associated with Evans syndrome
  - autoimmune disease such as systemic lupus erythematosus (SLE)
  - autoimmune lymphoproliferative syndrome
  - proliferative disorder or myelodysplasia by bone marrow biopsy
  - imaging by chest x-ray, abdominal ultrasound, positron emission tomography, or computed tomography to detect malignancy
tests to perform before commencing therapy
- primary immunodeficiency should be specifically tested before commencing steroids or IV immunoglobulin⁽³⁾
- blood group typing and RBC antigen phenotyping prior to RBC transfusion⁽¹⁾ (see Blood transfusion section for additional information)

Blood Tests

Complete Blood Cell Count

patients may present with⁽¹⁾
- anemia, typically normocytic or macrocytic, often hyperchromic
- normal or low reticulocyte count – reported in 40% of children with Evans syndrome
- thrombocytopenia
- neutropenia

Peripheral Blood Smear

peripheral blood smear may show⁽¹⁾
- spherocytes
- in cohort of 57 adults with Evans syndrome, features detected on peripheral blood smear at time of autoimmune hemolytic anemia (AIHA) onset included
  - spherocytes in 21 patients (37%)
  - schistocytes in 10 patients (17.5%)
  - Reference – Blood 2009 Oct 8;114(15):3167 full-text
- rouleaux (long chains for red blood cells [RBCs])

Direct Antiglobulin Test (Coombs Test)

direct antiglobulin test (DAT)
- detects immunoglobulins (Ig) and complement components bound to RBCs
- performed by adding antihuman globulin (AHG) which results in agglutination of sensitized RBCs
- AHG polyspecific or monospecific for IgG and anti-complement (usually C3d) can be used
- Reference – Autoimmun Rev 2014 Apr-May;13(4-5):560
to determine type of AIHA
- at minimum, perform DAT using monospecific anti-IgG and anti-C3d (BCSH Grade 1C)⁽²⁾
- polyspecific AHG may be used for the initial DAT, but if DAT is positive, monospecific AHG should be used to determine if IgG or complement is present (Autoimmun Rev 2014 Apr-May;13(4-5):560)
screening for cold reactive antibodies in patients who have tested positive for complement only or both complement and IgG by DAT
- perform DAT (without AHG) at room temperature (BCSH Grade 1C)⁽²⁾
- CLINICIANS’ PRACTICE POINT: Cold reactive antibodies may be identified by other methods approved by individual institutions.
DAT result⁽¹⁾
- usually positive for IgG or IgG and complement C3d (warm AIHA), but about 10% of patients reported to be negative
- less commonly positive for C3d (in cold AIHA)
in rare cases, patients with AIHA may have negative DAT results due to⁽²⁾
- low affinity and low levels of antibody
- RBCs bound by Ig that are not tested for in DAT (for example, IgA or IgM)
- tube DAT method may not be sensitive enough
- improper technique
- Reference – Semin Hematol 2015 Oct;52(4):304
patients with DAT negative results with unexplained hemolysis⁽²⁾
- eluate testing can be performed to identify antibody that may be of too low a level to be detected via standard DAT
- British Committee on Standards in Haematology (BCSH) recommendations
  - perform column agglutination DAT using monospecific anti-IgG and anti-complement or anti-IgA if available (BCSH Grade 1B)
  - if column agglutination DAT results is also negative, consider RBC eluate testing (BCSH Grade 2B)
- other DAT detection methods such as flow cytometry, enzyme-linked immunosorbent assay (ELISA), microcolumn agglutination test, solid-phase agglutination test, and mitogen-stimulated (MS)-DAT may be considered (may only be available at a reference laboratory)
- References
  - Semin Hematol 2015 Oct;52(4):304
  - Fung MK, Grossman, BJ, Hilyer CD, Westhoff, CM, eds. Technical manual of American Association of Blood Banks (AABB). 18th ed. Bethesda, MD: AABB; 2014

Other Blood Tests

patients may present with results indicative of hemolysis including^(1,2,3)
- increased lactate dehydrogenase (may be affected by disease progression or liver dysfunction in patients with hematological malignancy)
- low haptoglobin
- elevated bilirubin
consider additional tests for⁽¹⁾
- renal function including blood urea nitrogen and creatinine
- C-reactive protein
- partial thromboplastin time
- fibrinogen
- D-dimer
blood tests to consider to help determine underlying conditions for secondary Evans syndrome^(1,2)
- for all children, test for other immunological diseases before starting treatment (BCSH Grade 1A)
- testing to consider for all children or if suspected of Evans syndrome
  - liver function tests (BCSH Grade 2C for children)
  - flow cytometry for peripheral T-cell subsets
  - creatinine level
  - clotting assays
- consider testing for infections associated with Evans syndrome such as HIV, hepatitis C, Helicobacter pylori
- consider testing for parvovirus B19 and hematinics if patient has reticulocytopenia
- screening for autoimmune diseases such as systemic lupus erythematosus (SLE), including
  - antinuclear antibodies
  - anti-DNA antibodies
  - antiphospholipid antibodies
  - anti-Smith antibodies
  - antithyroglobulin antibodies
  - antithrombopoietin antibodies
- screening for autoimmune lymphoproliferative syndrome
  - double-negative T cells
  - vitamin B12
  - interleukin (IL) 10
  - IL-18
  - circulating apoptosis stimulating fragment
  - Fas apoptosis functional test
tests to consider prior to commencing therapy⁽¹⁾
- immunologic work up including
  - Ig levels
  - lymphocyte subsets
- blood group typing (ABO and Rh) and RBC antigen phenotyping for: C, c, D, E, e, K, Jk^a, Jk^b, Fy^a, Fy^b, S, s prior to RBC transfusion
dipstick and microscopy – may be positive for blood (hemoglobin) while urine microscopy negative for RBCs with intravascular hemolysis⁽²⁾
test for hemosiderin
- may be detected about 1 week after intravascular hemolysis⁽²⁾
- free hemoglobin is readily filtered by the renal glomeruli and is then reabsorbed by the proximal tubular cells where it is subsequently degraded into ferritin and hemosiderin; the hemosiderin is then excreted via urine (McPherson RA, Pincus MR. eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. Philadelphia, PA: Saunders; 2007)

Imaging Studies

consider chest x-ray and abdominal ultrasound (spleen, liver, lymph nodes) to rule out malignant disease^(1,2)
if patient presents significant lymphadenopathy or splenomegaly, consider positron emission tomography or computed tomography to detect malignancy⁽⁴⁾

Biopsy and Pathology

consider bone marrow biopsy to exclude a proliferative disorder or myelodysplasia⁽¹⁾

Management

Management Overview

goal of treatment is to control cytopenias while minimizing toxicity⁽¹⁾
in children^(1,4)
- disease is often relapsing/resistant to treatment or chronic, and may require prolonged treatment
- some require therapy only if disease flares
treatment options have not been evaluated by clinical trials, but are limited to case reports and retrospective studies with limited number of patients^(1,3)
patients with severe or life-threatening disease
- red blood cell (RBC) transfusion
  - if anemia is life-threatening, transfuse ABO, Rh (D, C, and E) and K matched RBCs, if possible, while full pretransfusion compatibility testing is being completed (BCSH Grade 1C)
  - identification of compatible donor is made difficult by broad reactivity of autoantibodies; choose best-matched RBC based on extensive RBC phenotyping
  - transfusion of children should be avoided unless signs of cardiac decompensation are present (BCSH Grade 2C)
- platelet transfusion – consider only for patients with life-threatening hemorrhages
- plasmapheresis rarely indicated for life-threatening cases not responding to transfusion; consider daily or alternate day exchange of 1-1.5 times plasma volume with albumin
- granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/dose) may be considered for severe neutropenia complicated by infections
first-line therapy for primary Evans syndrome
- administer corticosteroids or IV immunoglobulin (IVIG) as first-line treatment (BCSH Grade 1C)
  - corticosteroids
    - usually the main first-line therapy but patients often relapse
    - suggested dosing in children 1-6 mg/kg/day continued for ≥ 3-4 weeks, then slowly tapered over ≥ 6 months
  - IVIG
    - may be effective for patients who fail to respond to corticosteroids or require high doses to stay in remission and should be considered as adjuvant therapy in severe Evans syndrome associated with thrombocytopenia
    - dosing in children
      - CLINICIANS’ PRACTICE POINT: Most children receive 1g/kg IV 1 day; it may be repeated a second time (2 days total).
      - second option – 0.4-0.5 g/kg for 4-5 days
second-line therapy for primary Evans syndrome
- consider immunosuppressive drugs, danazol, rituximab, splenectomy, or vincristine (for treatment of thrombocytopenia) as second-line treatment (BCSH Grade 2C no preference for 1 treatment over another stated)
- also consider use of sirolimus for children who fail mycophenolate mofetil therapy or if steroid-sparing/maintenance treatment is needed
other therapies for primary Evans syndrome
- evidence for efficacy of other treatments such as cyclophosphamide, alemtuzumab, and hematopoietic stem cell transplantation is limited
- use of thrombopoietin receptor agonists such as romiplostim and eltrombopag is not approved for treatment for Evans syndrome; however, it may help increase platelet counts
for patients with secondary syndrome see Management of patients with secondary autoimmune hemolytic anemia section of Autoimmune Hemolytic Anemia for additional information

Medications

Corticosteroids

corticosteroids are usually the main first-line therapy, especially for children with acute flares or who are newly diagnosed; however, patients often relapse^(3,4)
in most children, disease is relapsing/resistant to therapy or chronic and may require prolonged treatment with steroids, which may lead to toxicities affecting bone and endocrine systems⁽¹⁾
administer corticosteroids or IV immunoglobulin (IVIG) as first-line treatment for primary Evans syndrome (BCSH Grade 1C)⁽³⁾
dosing options⁽¹⁾
- prednisolone
  - 1-6 mg/kg/day
  - continue full dose for ≥ 3-4 weeks, then slowly taper over ≥ 6 months
  - after 3 weeks, for children with
    - partial response, consider full dosage for additional 2 weeks
    - no response, consider second-line therapy options
- may also consider high-dose methylprednisolone
  - 30 mg/kg/day for 3 days, 20 mg/kg/day for the following 4 days and then tapering by half of the dose each week
  - CLINICIANS’ PRACTICE POINT: Methylprednisolone 2 mg/kg/dose every 6 hours as an intermediate dose schedule between high dose (30 mg/kg/day) and regular dose (for example, 2-4 mg/kg/day) can be considered.
complete response reported in 80%-85% of children, most treated with prednisolone 1-2 mg/kg/day⁽¹⁾
relapse reported to occur often, especially during tapering⁽¹⁾
in adult patients with Evans syndrome, corticosteroids reported to induce initial overall response in 82%, but 73% of all patients reported to require ≥ 1 second-line therapy (level 3 [lacking direct] evidence)
- based on case series
- 68 patients (60% women, mean age 55 years) with Evans syndrome were treated with corticosteroids as first-line therapy for management of AIHA and/or immune thrombocytopenia (ITP) were followed for mean 4.8 years
- definition of response
  - for AIHA, complete response defined as hemoglobin (Hb) ≥ 12 g/dL (120 g/L) in absence of transfusion without indications of hemolysis; partial response defined as Hb ≥ 10 g/dL (100 g/L) with increase of ≥ 2 g/dL (20 g/L) from baseline and persistent hemolysis
  - for ITP, complete response defined as normal platelet count (> 150 × 10⁹/L); partial response defined as platelet count > 50 × 10⁹/L with ≥ 2-fold increase of pretreatment count
- for patients receiving corticosteroids to manage
  - AIHA (64 patients), initial overall response in 83%
  - ITP (54 patients), initial overall response in 82%
- ≥ 1 second-line therapy administered in 73% of all patients (including patients treated with corticosteroids or IVIG as first-line therapy)
- Reference – Blood 2009 Oct 8;114(15):3167 full-text

Rituximab

monoclonal antibody against the CD20 molecule that causes B-cell depletion⁽¹⁾
typical dose – 375 mg/m² on days 1, 8, 15, and 22⁽¹⁾
consider rituximab as second-line treatment in patients with primary Evans syndrome (BCSH Grade 2C)⁽³⁾
carefully consider use of rituximab for patients with autoimmune lymphoproliferative syndrome (ALPS)⁽¹⁾
- response rates reported to be lower
- higher risk of infection and prolonged hypogammaglobulinemia reported
rituximab reported to induce overall response in 73%-76% of children and 82% of adults with Evans syndrome (level 3 [lacking direct] evidence)
- based on 1 uncontrolled trial and 1 case series
- 61 children (median age 5.5 years) with AIHA were treated with rituximab 375 mg/m²/week for 4 weeks
  - 46 children had isolated AIHA
  - 15 children had Evans syndrome (10 children presented with ITP prior to AIHA, 5 children had ITP and AIHA simultaneously)
  - all children received steroid treatment (median dose 2 mg/kg/day) before rituximab; rituximab was given because they were either nonresponsive or partially responsive to steroids, or relapsed after steroid treatment
  - partial response defined as Hb 7-11 g/dL (70-110 g/L) and/or reticulocytosis > 120 × 10⁹/L
  - complete response defined as Hb ≥ 11 g/dL (110 g/L) and reticulocytosis ≤ 120 × 10⁹/L irrespective of direct antiglobulin test result and therapy
  - for patients with Evans syndrome
    - overall response in 73%
    - complete response in 46%
    - 6-year relapse free survival 36%
  - Reference – Br J Haematol 2017 Jun;177(5):751
- 11 adults with Evans syndrome were treated with rituximab and followed for mean 4.8 years
  - 7 patients received rituximab for chronic severe corticosteroid-depending or refractory ITP
  - 3 patients received rituximab for severe or relapsing AIHA
  - 1 patient received rituximab as part of long-term therapy with corticosteroids to maintain partial response of AIHA and ITP
  - definition of response
    - for AIHA, complete response defined as Hb ≥ 12 g/dL (120 g/L) in absence of transfusion without indications of hemolysis; partial response defined as Hb ≥ 10 g/dL (100 g/L) with increase of ≥ 2 g/dL (20 g/L) from baseline and persistent hemolysis
    - for ITP, complete response defined as normal platelet count (> 150 × 10⁹/L); partial response defined as platelet count > 50 × 10⁹/L with ≥ 2-fold increase of pretreatment count
  - initial overall response in 9 patients (82%)
  - long-term overall response in 7 patients (64%) at 12 months
  - Reference – Blood 2009 Oct 8;114(15):3167 full-text

Immunosuppressive Drugs

General Considerations for use of Immunosuppressive Drugs

consider immunosuppressive drugs such as mycophenolate mofetil (MMF), cyclosporine, or azathioprine as options for second-line therapy (BCSH Grade 2C without preference for 1 drug over another stated)⁽³⁾
sirolimus
- consider for children who fail MMF therapy, or if steroid-sparing/maintenance treatment is needed⁽¹⁾
- CLINICIANS’ PRACTICE POINT: Some clinicians may prefer to use sirolimus as the first choice among immunosuppressive agents.
cyclophosphamide may be a treatment option for patients who fail second-line therapies, but there is limited evidence of efficacy in patients with Evans syndrome^(1,3)
patients who do not respond to single immunosuppressive drug may benefit from multiagent treatment⁽³⁾

Mycophenolate Mofetil (MMF)

reduces T, B, and natural killer-cell proliferation by inhibiting inosine monophosphate dehydrogenase in purine synthesis⁽¹⁾
reported to be effective in patients with AIHA or ITP⁽¹⁾
may be effective for patients with Evans syndrome associated with ALPS⁽¹⁾
suggested dose⁽¹⁾
- 600 mg/m²twice daily and maintain serum levels at 1-3.5 mcg/mL
- if there is a response, continue treatment for 2 years at full dose then taper over 6 months
requires long time to achieve response; consider overlapping therapy with high-dose steroids or rituximab for children who are relapsing or steroid-dependent and need drug sparing therapy, or are experiencing flare-ups during tapering
mycophenolate mofetil reported to induce overall response in 81% of children with Evans syndrome
- based on case series
- 16 children with Evans syndrome were treated with MMF for median 7 months and followed for median 12.7 months
  - 5 children had primary Evans syndrome; 11 children had ALPS-associated Evans syndrome
  - 13 children had no prior treatment; 3 children were previously treated with cyclosporine A
  - 6 children were concomitantly treated with corticosteroids
- complete response (platelet count ≥ 100 × 10⁹/L) in
  - 13 children (81%) overall
  - 4 children (80%) with primary Evans syndrome
  - 9 children (82%) with ALPS-associated Evans syndrome
- relapse in 1 child at median 283 days (2 months after end of 1 year course of MMF)
- Reference – Br J Haematol 2016 Nov;175(3):490

Cyclosporine

while BSH suggests cyclosporine as 1 option for second-line therapy, cyclosporine may be considered after failure with other treatments such as MMF or sirolimus⁽¹⁾
may be used concomitantly with other therapies in severe refractory cases only, after failing other targeted treatments such as rituximab⁽¹⁾
typical dose in adults and children 5 mg/kg/day⁽¹⁾
alternate-day cyclosporine and prednisone treatment reported to improve anemia and thrombocytopenia in 12-year-old boy with Evans syndrome refractory to multiple therapies in case report (Pediatr Int 1999 Feb;41(1):104)

Azathioprine and Other Thiopurines

azathioprine and other thiopurines
- limited evidence for efficacy⁽³⁾
- CLINICIANS’ PRACTICE POINT: While there is limited evidence for efficacy, azathioprine is widely used.

Sirolimus

inhibitor of the mammalian (mechanistic) target of rapamycin, resulting in apoptosis in abnormal lymphocytes⁽¹⁾
consider in those who fail MMF therapy⁽¹⁾
typical starting dose in children is 2-3 mg/m² once daily⁽¹⁾
dose is titrated to maintain serum levels between 4 and 12 ng/mL, with an optimal target of 9 ng/mL⁽¹⁾
sirolimus reported to induce response in patients with Evans syndrome refractory to other therapies
- based on 1 uncontrolled trial and 1 case series
- 30 children and young adults (median age 11 years) with autoimmune cytopenias refractory or nonresponsive to other therapies were treated with sirolimus 2-2.5 mg/m²/day (maximum initial dose 4 mg/day) and followed for median 2 years
  - 8 patients had Evans syndrome
  - prior therapies included corticosteroids, IV immunoglobulin, mycophenolate mofetil, rituximab, or granulocyte colony-stimulating factor
  - at 3 months
    - complete response (resolution of cytopenia and lymphoproliferation) in 3 patients
    - partial response in 3 patients
    - no response in 2 patients
  - at 12 months
    - complete response in 4 patients
    - no response in 1 patient
    - off study in 3 patients
  - Reference – Blood 2016 Jan 7;127(1):17 full-text, editorial can be found in Blood 2016 Jan 7;127(1):5
- 17 patients (age 6-21 years) with autoimmune cytopenias refractory to previous therapies were treated with sirolimus and followed for median 2.25 years
  - 5 with Evans syndrome and 12 with immune thrombocytopenia
  - sirolimus given 2-2.5 mg/m²/day orally, titrated up to 4 mg/day based on clinical response and tapered over 4 months after achieving response; steroids were concurrently administered
  - previous therapies included corticosteroids, IVIG, azathioprine, cyclosporine
  - definition of response
    - complete response defined as platelet count > 150 × 10⁹/L, normal Hb level for ≥ 2 months with tapering of steroids
    - partial response defined as improvement of cytopenias by ≥ 1 grade of common terminology criteria for adverse events for ≥ 2 months with same dose or tapering of steroids or stable cell count while tapering steroids by ≥ 50%
    - modest response defined as increase in platelet count from < 10 × 10⁹/L to 10-20 × 10⁹/L and asymptomatic
  - all patients with Evans syndrome had response
    - complete response in 2 patients; 1 patient at 3 months and 1 patient at 9 months
    - durable partial response in 2 patients for both platelet count and hemoglobin by 3 months
    - modest initial response in 1 patient, but sirolimus discontinued due to hematuria
  - Reference – J Pediatr Hematol Oncol 2017 Aug;39(6):420

Cyclophosphamide

limited evidence for use in patients with Evans syndrome⁽¹⁾
example dosing 1-2 mg/kg orally for 2-3 months or 200 mg/kg IV in 4 days⁽¹⁾
high-dose cyclophosphamide (50 mg/kg/day for 4 days) reported to induce improvement in blood counts and resolution of symptomatic manifestations in 31-year-old man with refractory, severe Evans syndrome in case report (Ann Intern Med 1998 Dec 15;129(12):1031)

IV Immunoglobulins (IVIG)

functions by binding to fragment crystallizable phagocyte receptors in the reticuloendothelial system and inhibiting uptake of opsonized red blood cells or platelets⁽¹⁾
administer corticosteroids or IVIG as first-line treatment (BCSH Grade 1C)⁽³⁾
IVIG may be effective for patients who fail to respond to corticosteroids or require high doses to stay in remission⁽³⁾
consider as adjuvant therapy in severe Evans syndrome associated with thrombocytopenia⁽¹⁾
dosing for children
- CLINICIANS’ PRACTICE POINT: Most children receive 1g/kg IV 1 day; it may be repeated a second time (2 days total).
- second option – 0.4-0.5 g/kg for 4-5 days⁽¹⁾
IVIG reported to induce response in some patients (mostly children) with Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 42 patients (median age 7.7 years at presentation) with Evans syndrome receiving various therapies were followed for median 3 years
  - patients received median 5 treatments in combination or sequentially
  - 40 patients received ≥ 1 course of IVIG
- complete response (Hb > 12 g/dL [120 g/L] and platelet count > 150 × 10⁹/L sustained for ≥ 6 months) in 9 patients with response lasting as long as 2 years (patients also received corticosteroids)
- no response to 1 course of IVIG in 5 patients
- refractory to IVIG after 2 courses of IVIG in 2 patients
- transient response lasting 2-4 weeks in 24 patients
- Reference – J Pediatr Hematol Oncol 1997 Sep-Oct;19(5):433, commentary can be found in J Pediatr Hematol Oncol 1999 May-Jun;21(3):248
IVIG reported to induce initial overall response in 60% of adult patients with Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 33 adults with Evans syndrome were treated with IVIG as first-line treatment for management of immune thrombocytopenia and followed for mean 4.8 years
- complete response defined as normal platelet count (> 150 × 10⁹/L); partial response defined as platelet count > 50 × 10⁹/L with ≥ 2-fold increase of pretreatment count
- initial overall response in 20 patients (60%)
- Reference – Blood 2009 Oct 8;114(15):3167 full-text

Granulocyte Colony-stimulating Factor (G-CSF)

consider G-CSF 5 mcg/kg/dose for severe neutropenia complicated by severe infections⁽¹⁾
available as filgrastim (Blood 2014 Aug 21;124(8):1251 full-text)

Other Medications

Thrombopoietin (TPO) Receptor Agonists

TPO receptor agonists (romiplostim and eltrombopag) are used in treatment of some hematological disorders⁽¹⁾
stimulates platelet production by activating TPO receptor (Blood 2010 Jan 14;115(2):168 full-text)
may induce a response in patients with Evans syndrome, but not approved for use in these patients⁽³⁾
romiplostim (1 mcg/kg/week subcutaneously for 2 weeks, followed by 2 mcg/kg/week for 2 weeks) reported to increase platelet count in 44-year-old man with Evans syndrome and severe thrombocytopenia refractory to rituximab in case report (Lupus 2011 Oct;20(12):1321)

Alemtuzumab

humanized anti-CD52 monoclonal antibody targeting T and B lymphocytes, eosinophils, and monocytes⁽¹⁾
may be a treatment option for patients who fail second-line therapy, but limited evidence for efficacy in patients with Evans syndrome^(1,3)
most patients reported to relapse after initial response⁽¹⁾
dosing options include 10 mg/m²/day for 10 days or 0.2 mg/kg for 5 days⁽¹⁾
alemtuzumab reported to induce initial response in patients with Evans syndrome, but patients reported to relapse (level 3 [lacking direct] evidence)
- based on case series
- 21 patients with severe life-threatening autoimmune cytopenias (3 patients [ages 15, 24, and 60 years] with Evans syndrome) and treated with alemtuzumab 10 mg/day IV for 10 days were evaluated
- response defined as sustained platelet count > 30 × 10⁹/L for ≥ 3 months, RBC transfusion independence, discontinuation of corticosteroid
- outcomes in patients with Evans syndrome included
  - response in 1 patient at week 1 but relapsed at 3 months; response to second course of treatment at 1 week, but relapsed at 19 months
  - response in 1 patient at day 3 but relapsed at 3 months; response to second course of treatment at 2 weeks
  - transient response only in 1 patient
- death in 2 patients; 1 patient from cerebral hemorrhage and 1 patient from recurrent bronchial carcinoma
- Reference – Br J Haematol 2001 Sep;114(4):891

Danazol

synthetic anabolic steroid with mild androgenic properties (Haematologica 2014 Oct;99(10):1547 full-text)
consider danazol as 1 of the options for second-line therapy (BCSH Grade 2C)⁽²⁾
limited evidence for efficacy in patients with Evans syndrome⁽³⁾
typical dose 200 mg 3-4 times daily with prednisolone (adult dosing)⁽²⁾
danazol reported to induce response in 60% of adult patients with Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 23 adults with Evans syndrome were treated with danazol as second-line therapy and followed for median 4.8 years
- overall response in 60%
- Reference – Blood 2009 Oct 8;114(15):3167 full-text

Vincristine

consider vincristine as 1 of the options for second-line therapy (BCSH Grade 2C)⁽³⁾
mitotic inhibitor targeting B, T, and natural killer cells⁽⁴⁾
used to treat thrombocytopenia⁽³⁾
consider in combination with other therapies⁽³⁾

Blood Transfusion

Red Blood Cell (RBC) Transfusion

General Considerations for Red Blood Cell (RBC) Transfusion

decision to transfuse should be reserved for very symptomatic patients, rather than based on hemoglobin level, with the goal of correcting clinical symptoms⁽¹⁾
British Society for Haematology (BSH) recommendations for RBC transfusion^(2,3)
- if anemia is life-threatening, transfuse ABO, Rh (D, C, and E), and K matched RBCs if possible, while full pretransfusion compatibility testing is being completed (BCSH Grade 1C)
- transfusion of children should be avoided unless signs of cardiac decompensation are present (BCSH Grade 2C)

Compatibility Testing and Selection of RBC Units Transfuse to Patients with Evans Syndrome

identification of compatible donor is made difficult by broad reactivity of autoantibodies; choose best-matched RBC based on extensive RBC phenotyping⁽¹⁾
slowly transfuse small amounts of leukocyte reduced RBCs (3 mL/kg)⁽¹⁾
testing for RBC unit compatibility may be further complicated if recipient has been transfused in past 3 months
- test plasma or serum with selected reagent RBC panel after allogeneic adsorption
- recipient may have developed alloantibodies to high-prevalence or multiple antigens as a result of previous transfusion; eluate should be tested with selected reagent RBC panel (may require alloadsorption)
- Reference – Fung MK, Grossman, BJ, Hilyer CD, Westhoff, CM, eds. Technical manual of American Association of Blood Banks (AABB). 18th ed. Bethesda, MD: AABB; 2014

Platelet Transfusion

consider platelet transfusions only for patients with life-threatening hemorrhages⁽¹⁾

Splenectomy

consider splenectomy as 1 of the options for second-line therapy (BCSH Grade 2C)⁽³⁾
CLINICIANS’ PRACTICE POINT: Splenectomy may be a better option for treatment of low platelet count rather than hemolytic anemia.
should only be considered only after the failure of other alternative drugs available for refractory patients⁽¹⁾
should be avoided in patients with autoimmune lymphoproliferative syndrome and children < 6 years old⁽¹⁾
initial response reported in 86% and 1-year response reported in 43% of adults having splenectomy for Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 7 adults (71% female) who had splenectomy for Evans syndrome were evaluated
- response was defined as improvement in hematocrit and platelet count to within normal laboratory limits
- clinical outcomes
  - initial response in 6 patients (85.7%)
  - loss of response within 1 year necessitating additional medical therapy in 3 patients (42.8%)
  - 1-year response in both hematocrit and platelet count after splenectomy in 3 patients (42.8%)
- Reference – Eur J Haematol 2020 Jan;104(1):55 full-text
splenectomy reported to induce response in 78% with long-term response in 52% of adult patients with Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 19 adults with Evans syndrome who had splenectomy were followed for mean 8 years
  - 11 patients had chronic severe immune thrombocytopenia (ITP)
  - 6 patients had persistent autoimmune hemolytic anemia (AIHA)
  - 2 patients had both conditions
- definition of response for
  - AIHA – complete response defined as sustained hemoglobin (Hb) > 12 g/dL (120 g/L) in absence of transfusion without indications of hemolysis; partial response defined as Hb ≥ 10 g/dL (100 g/L) with increase of ≥ 2 g/dL (20 g/L) from baseline and persistent hemolysis
  - ITP – complete response defined as platelet count > 150 × 10⁹/L; partial response defined as platelet count > 50 × 10⁹/L with ≥ 2-fold increase of pretreatment count
- overall response (complete and partial response) in 15 patients (78%) at 1 month
- long-term response in 10 patients (52%) at mean 8 years
- death due to sepsis in 1 patient at day 21
- Reference – Blood 2009 Oct 8;114(15):3167 full-text
splenectomy reported to increase platelet count and hemoglobin levels in patients (mostly children) with Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 42 patients (median age 7.7 years at presentation) with Evans syndrome receiving various therapies were evaluated
  - patients received median 5 treatments in combination or sequentially
  - 15 patients (median age 10 years) had splenectomy due to thrombocytopenia (6 patients), hemolytic anemia (5 patients), or both conditions (4 patients)
- median duration of response 1 month
  - increase in platelet count in 7 patients
  - normalization of platelet count in 2 patients
  - increase in Hb in 6 patients
  - complete response (Hb > 12 g/dL [120 g/L] and platelet count > 150 × 10⁹/L sustained for ≥ 6 months) in 1 patient
- Reference – J Pediatr Hematol Oncol 1997 Sep-Oct;19(5):433, commentary can be found in J Pediatr Hematol Oncol 1999 May-Jun;21(3):248

Other Management

Plasmapheresis

plasmapheresis (plasma exchange) rarely indicated for patients with Evans syndrome; may be considered for life-threatening cases not responding to transfusion⁽¹⁾

Hematopoietic Stem Cell Transplantation (HSCT)

consider HSCT for patients with relapsing or therapy-resistant Evans syndrome in life-threatening condition⁽¹⁾
complete remission reported in about 50% of patients with autoimmune hemolytic anemia and Evans syndrome⁽¹⁾
HSCT reported to induce remission in some patients with refractory Evans syndrome (level 3 [lacking direct] evidence)
- based on case series
- 36 patients with refractory autoimmune cytopenia having HSCT (38 transplants total) were followed for ≥ 3 months post transplantation
  - 27 patients (median age 31 years) had autologous HSCT
  - 9 patients (median age 14 years) had allogeneic HSCT
  - 7 patients had Evans syndrome; 2 patients received autologous HSCT and 5 patients received allogeneic HSCT
- complete response defined as hemoglobin (Hb) > 12 g/dL (120 g/L), neutrophil count > 1.5 × 10⁹/L, and platelet count > 150 × 10⁹/L
- partial response defined as Hb > 8 g/dL (80 g/L), neutrophil count > 0.5 × 10⁹/L, and platelet count 50 × 10⁹/L
- outcome of autologous HSCT in patients with Evans syndrome
  - transient response in 1 patient
  - continuous response in 1 patient
- outcome of allogeneic HSCT in patients with Evans syndrome
  - treatment related mortality in 1 patient
  - mortality due to progression of disease in 1 patient
- Reference – Autoimmunity 2008 Dec;41(8):660

Complications and Prognosis

Complications

venous thromboembolism (VTE) – more likely to occur in patients with active hemolysis⁽²⁾
myelodysplastic syndrome, B-cell lymphoma, and cardiovascular manifestations may develop in patients with Evans syndrome
- based on cohort study
- 68 adult patients (mean age of disease onset 55 years) with Evans syndrome from France and Italy with mean follow-up 4.8 years
- among patients with primary Evans syndrome (34 patients)
  - myelodysplastic syndrome developed in 2 patients
  - B-cell lymphoma in 1 patient
- among patients > 60 years old at time of autoimmune hemolytic anemia diagnosis (28 patients)
  - cardiovascular manifestation in 6 patients, including
    - myocardial infarction in 1 patient
    - acute coronary syndromes in 4 patients
    - stroke in 1 patient
- Reference – Blood 2009 Oct 8;114(15):3167 full-text

Prognosis

mortality 10% at median age 14.3 years in children with Evans syndrome, mainly due to infections and bleeding
- based on cohort study
- 156 children (median age of onset 5.4 years) with Evans syndrome from France were followed for median 6.5 years
- complete remission defined as platelet count > 100 g/L or hemoglobin ≥ 11g/dL (110 g/L) with reticulocytes < 120 g/L, and ongoing treatment or end of treatment since < 12 months
- mortality 10% at median age 14.3 years
- mortality due to
  - infections (suspected to be related to disease or treatments) in 70%
  - disease related causes in 30%, including bleeding in 27%
  - acute anemia in 0%
- relapse free survival (RFS) in patients with
  - autoimmune hemolytic anemia (AIHA) 2-year RFS 74%; 5-year RFS 61%
  - immune thrombocytopenia (ITP) 2-year RFS 32%; 5-year RFS 25%
- at last follow-up (median age 16.1 years) continuous complete remission (complete remission without treatment for ≥ 12 months) or complete remission for both ITP and AIHA in 74%
- Reference – Front Pediatr 2015 Sep 29;3:79 full-text
pathogenic or probably pathogenic mutations may be associated with increased likelihood of immunopathological manifestations in children with early-onset Evans syndrome
- based on prospective cohort study
- 80 children (median age 8 years) with early-onset Evans syndrome from OBS’CEREVANCE cohort who had genetic testing for candidate genes associated with primary immunodeficiencies were evaluated
- median follow-up from diagnosis was 6.7 years
- genetic findings
  - 65% had genetic defects
    - 40% had pathogenic mutations in 9 genes involved in primary immunodeficiencies
    - 25% had probably pathogenic mutations in 16 genes not previously reported for autoimmune diseases
  - 35% had no genetic defects
- genes with pathogenic mutations included TNFRSF6, CTLA4, STAT3, PIK3CD, LRBA, RAG1, and KRAS
- genes with probably pathogenic mutations encoded immune cell receptors (IFNAR1, TNFR2, and/or TGFBR2), transcription factors (IKZF1, NFATC1, and/or IKZF2), and proteins involved in apoptosis regulation (RIPK2, and/or APAF1), or intracellular signaling (JAK1, JAK2, PLCG2, TRAF3, CARD11, ARHGEF4, PTPN11, and/or PARP4)
- comparing children with genetic defects vs. without genetic defects
  - immunopathological manifestations in 92% vs. 64% (p = 0.001)
  - median number of immunopathological manifestations 2.5 vs. 1 (p = 0.007)
  - hypogammaglobulinemia in 56% vs. 29% (p = 0.02)
  - autoimmune/autoinflammatory organ disease in 56% vs. 32% (p = 0.04)
  - median number of second-line treatments 2 vs. 1 (p = 0.02)
  - mortality 12% vs. 0% (p = 0.086)
- Reference – Blood 2019 Jul 4;134(1):9 full-text
20% mortality reported in adults with Evans syndrome
- based on retrospective cohort study
- 116 adults (median age at diagnosis 51 years, range 1.9-94.8 years) with Evans syndrome from 13 centers in Europe were followed for median of 7.5 years
  - 79% of patients had primary Evans syndrome, and 21% had Evans syndrome secondary to or associated with other conditions, including other autoimmune conditions, hematologic neoplasms, and primary immunodeficiencies
  - 81% had ITP and AIHA; 10% had ITP, AIHA, and autoimmune neutropenia (AIN); and 9% had ITP and AIN or AIHA and AIN
- outcomes
  - mortality 20%
  - bleeding in 42%
  - infection in 33%
  - thrombosis in 21%
  - ≥ 2 lines of therapy in 76%
  - ≥ 3 lines of therapy in 54%
- relapse, thrombosis, and infection each associated with increased risk of death in multivariate analysis
- Reference – Blood Adv 2021 Dec 28;5(24):5468 full-text
disease remission with or without ongoing treatment reported in 78% of adult patients with Evans syndrome
- based on cohort study
- 68 adults (mean age of disease onset 55 years) with Evans syndrome from France and Italy had mean follow-up 4.8 years
- outcomes included
  - remission and off treatment in 32%
  - remission on but on treatment in 56%
  - active disease in 12%
  - mortality in 24% at mean age 72.2 years; none due to bleeding
- Reference – Blood 2009 Oct 8;114(15):3167 full-text

Prevention and Screening

not applicable

Guidelines and Resources

Guidelines

British Society for Haematology (BSH):
- BSH guidelines on diagnosis and management of primary autoimmune haemolytic anaemia can be found in Br J Haematol 2017 Feb;176(3):395.
- BSH guidelines on management of drug-induced immune and secondary autoimmune, haemolytic anaemia can be found in Br J Haematol 2017 Apr;177(2):208.

Review Articles

review of autoimmune and other cytopenias in primary immunodeficiencies can be found in Blood 2014 Oct 9;124(15):2337 full-text
review of autoimmune lymphoproliferative disorder and other secondary immune thrombocytopenias in childhood can be found in Pediatr Blood Cancer 2013;60 Suppl 1:S12
review of management of Evans syndrome can be found in Br J HaematolH 2006 Jan;132(2):125
review of treatment of refractory immune thrombocytopenia and Evans syndrome by hematopoietic stem cell transplantation can be found in Vox Sang 2016 Jan;110(1):5 full-text
review of clinical applications of hemolytic markers in differential diagnosis and management of hemolytic anemia can be found in Dis Markers 2015;2015:635670 full-text
case presentation can be found in Hematology 2008 Dec;13(6):356

MEDLINE Search

to search MEDLINE for (Evans syndrome) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information

information from Genetic and Rare Diseases Informaiton Center (GARD)
information from National Organization for Rare Disorders

References

General References Used

The references listed below are used in this DynaMed topic primarily to support background information and for guidance where evidence summaries are not felt to be necessary. Most references are incorporated within the text along with the evidence summaries.

Miano M. How I manage Evans Syndrome and AIHA cases in children. Br J Haematol. 2016 Feb;172(4):524-34.
Hill QA, Stamps R, Massey E, et al; British Society for Haematology. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017 Feb;176(3):395-411.
Hill QA, Stamps R, Massey E, et al; British Society for Haematology. Guidelines on the management of drug-induced immune and secondary autoimmune, haemolytic anaemia. Br J Haematol. 2017 Apr;177(2):208-220.
Teachey DT, Lambert MP. Diagnosis and management of autoimmune cytopenias in childhood. Pediatr Clin North Am. 2013 Dec;60(6):1489-511 full-text.