Autoimmune hemolytic anemia management in adults: Consensus recommendations

Autoimmune hemolytic anaemias (AIHAs) are rare and heterogeneous disorders characterized by the destruction of red blood cells through warm or cold antibodies. There is currently no licensed treatment for AIHA.The international consensus recommendations have appeared in the Journal Blood Reviews.

AIHA is a heterogeneous group of diseases that should be treated differently.A thorough diagnostic workup is required to characterize the subtype of AIHA and select the appropriate treatment. Corticosteroids remain first-line therapy in wAIHA. Addition of rituximab in the first line should be considered in selected patients.In most patients with wAIHA, rituximab (if not given first-line) should be the preferred second-line therapy.In patients with CAD requiring treatment, first-line options are rituximab monotherapy or rituximab plus bendamustine, depending on individual patient characteristics.

Recommendations for diagnosis of AIHA:

• All patients should have baseline values of LDH, bilirubin, haptoglobin, reticulocyte count, and review of peripheral smear (looking for spherocytes with wAIHA, RBC aggregation with CAD, and schiztocytes to exclude thrombotic microangiopethies) (99% agreement).


• The direct antiglobulin test (DAT) should be performed with monospecific antisera (anti-IgG, anti-IgA, anti-IgM, anti-C) (96% agreement).


• It is advisable to consider that about 5–10% of AIHAs may be DAT negative (85% agreement).


• In case of DAT negativity, other causes of congenital or acquired haemolysis should be considered, but if no alternative is found, the DAT should be performed with more sensitive methods in a reference center (99% agreement). If sensitive tests are not available, a trial of corticosteroids may be considered.


• All wAIHA patients should be evaluated for underlying autoimmune diseases (ANA, RF, antiphospholipid antibody), lymphoproliferative disorders (flow cytometry of peripheral blood, review of peripheral blood smear, possible CT scan assessing for lymphadenopathy and splenomegaly) or immune deficiency (serum protein electrophoresis with immunofixation) disorders (93% agreement).


• Diagnosis of CAD should include DAT (C3d+), a cold agglutinin titre and bone marrow examination (at least by histology and flow cytometry) (87% agreement).


• Primary CAD should be differentiated from secondary CAS (88% agreement).


• All patients with suspected CAD should be evaluated for clonal B cell disorder with SPEP, immunofixation, peripheral blood and bone marrow flow cytometry, bone marrow biopsy, and, if indicated, CT scans looking for lymphadenopathy and splenomegaly (96% agreement).


• Baseline assessment for signs of acrocyanosis in patients with CAD (93% agreement).


• In patients with DAT positive for IgG and C3 and presence of symptoms of CAD, mixed AIHA should be considered and diagnosed by performing CA test and titer (92% agreement).


• Diagnostic uncertainty after AIHA evaluation in a patient with fitting history should elicit the performance of a Donath–Landsteiner biphasic test in an experienced laboratory (77% agreement).


• In a patient with hemolysis and DAT negativity, other non-immune types of haemolysis should be excluded; if none are found, atypical AIHA should be considered and pursued with appropriate diagnostic tools in reference centers. Clinical severity and increased relapse risk should be taken into consideration (90% agreement).

Recommendations for treatment of primary wAIHA:

• The indication for treatment of wAIHA is symptomatic anaemia. Exceptionally, in the rare patients with mild and stable anemia, monitoring may be appropriate (“W&W”) .(100% agreement).


• First line treatment for warm AIHA is oral predniso(lo)ne starting at 1 mg/kg daily. Prednisone-rituximab may be considered front-line in selected patients with severe disease or in elderly patients with comorbidities (100% agreement).


• In patients responding to predniso(lo)ne at a dose ≥1 mg/kg, begin to taper after 14–21 days. Also begin to taper by 21 days in unresponsive patients. For patients responding well to prednisone consider stopping the treatment after at least 3 months after a complete response is achieved (see response criteria). Consider second line treatment in unresponsive patients and those relapsing as the steroid is weaned (100% agreement).


• The preferred second line therapy for wAIHA is rituximab 375 mg/m² weekly for 4 weeks. An alternative regimen of 1 g day 1 and 15 may also be considered. For patients receiving rituximab first line, re-treatment may be considered in patients with a response of meaningful duration (e.g., 1 year or more), otherwise consider third line treatments (96% agreement).


• Third line treatment options include splenectomy, azathioprine, cyclosporin and mycophenolate and should be based on the individual assessment of the benefit over risk ratio (95% agreement).


• Patients with chronic refractory wAIHA not responding to at least 3 treatment-lines (including splenectomy and or at least one immunosuppressant) should be referred to a specialized center and whenever possible treated in the setting of a clinical trial (99% agreement).


• Other lines of therapy to be considered are cyclophosphamide, continuous low dose prednisone, danazol, haematopoietic stem cell transplantation, and bortezomib (82% agreement).


• Management of transfusion-dependent life-threatening wAIHA must combine supportive therapies (ESA ± plasma exchange and/or IVIg), active immunosuppression, and emergency splenectomy/embolization. Thromboprophylaxis is also indicated in order to minimize the risk of venous thrombosis (97% agreement).

Recommendations for treatment of secondary wAIHA:

• Management of CLL-associated wAIHA must take into account the stage and activity of CLL. Patients with stage A CLL can be managed as primary wAIHA, whereas for patients with active CLL, combination therapies including rituximab + chemotherapy ± dexamethasone should be considered. Kinase inhibitors should be preferred in patients with TP53 aberration and considered in other refractory cases. The use of fludarabine or chlorambucil as a single agent should be avoided (100% agreement).


• Rituximab is a relevant option for the management of corticosteroid-refractory or dependent SLE-associated wAIHA. In case of rituximab refractoriness or severe non-hematologic manifestations, mycophenolate mofetil may be effective. Splenectomy should be avoided, especially for patient with an associated antiphospholipid antibody syndrome, particularly regarding splenectomy) (88% agreement).


• Rituximab can be considered as a second-line and corticosteroid-sparing strategy for the treatment of CVID-associated wAIHA. Maintenance immunoglobulin replacement is strongly recommended in patients receiving corticosteroids, other immunosuppression and following splenectomy even without a history of severe or recurrent infections (98% agreement).

Patients with wAIHA not responding to first-line treatment, patients with CAD requiring therapy, and patients with rarer AIHAs should be considered for clinical trials if available.

For further reference log on to: https://doi.org/10.1016/j.blre.2019.100648