Current treatment strategies in autoimmune hemolytic disorders

Abstract

Autoimmune hemolytic anemia (AIHA) is a heterogeneous disease usually classified according to the thermal range of the autoantibody in warm, cold and mixed forms. The treatment of AIHA is still not evidence-based. Corticosteroids are the first-line therapy for warm AIHA. For refractory/relapsed cases, the choice is between splenectomy (effective in ∼70% cases but with a presumed cure rate of 20%) and rituximab (effective in ∼70–80% of cases), which is becoming the preferred second-line treatment, and thereafter any of the immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporin, mycophenolate mofetil). Additional therapies are intravenous immunoglobulins and danazol. For severe or refractory cases, last option treatments are plasma-exchange, high-dose cyclophosphamide and alemtuzumab. As regards cold agglutinin disease, rituximab is now recommended as first-line treatment.

Keywords:

• autoantibodies
• autoimmune hemolytic anemia
• cold agglutinin disease
• therapeutic options
• treatment

Financial & competing interests disclosure

This work was supported by research funding from Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, grant number RC 2014 and by Ministry of Health, grant number RF 2010 convention N. 141/RF-2010-2303934. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Autoimmune hemolytic anemia (AIHA) is classified in warm (∼70% of cases, direct antiglobulin test [DAT] positive for IgG or IgG + C), cold (∼20% of patients, DAT positive for C) and mixed forms. Atypical cases (mainly DAT-negative and warm IgM), warm IgG + C, mixed and secondary forms (lymphoproliferative syndromes, post-hematopoietic stem cell transplantation) are frequently severe, refractory to therapy and have a higher mortality than primary AIHAs.

• For warm AIHAs, steroids represent the first-line therapy able to provide a response in 70–85% of patients, but with an estimated cure rate in 20–30% only. Second-line treatment includes splenectomy (early response rate ∼70%, and presumed curative rate ∼20%) and rituximab (response rate 70–80% and disease-free survival of ∼70% at 1 and ∼55% at 2 years). Cons of splenectomy are the associated infective and thrombotic risk, and the surgical complications (reduced with the laparoscopic approach), particularly in patients older than 65–70 years and with associated comorbidities. Rituximab is increasingly preferred among second-line treatments, alone or in combination with various drugs. Predictors of response are younger age, and early administration as second-line therapy, particularly in severe/acute forms, including post-transplant cases.

• Further treatments include conventional immunosuppressive drugs (azathioprine, cyclophosphamide, cyclosporine), with response rates of 40–60%, and mycofenolate (effective in ∼90% of refractory immune cytopenias in children, and in post-hematopoietic stem cell transplant). For the few ultra-refractory patients, last-option treatments include high dose cyclophosphamide and alemtuzumab, whose efficacy is anecdotal. Plasma-exchange may be useful in critical and very severe AIHA, and erythropoietin indicated in the presence of reticulocytopenia to avoid hemolysis related to overtransfusion.

• In cold agglutinin disease (CAD), steroids are now discouraged as they are effective at unacceptably high doses and in a small fraction of cases (14–35%), and splenectomy is usually unsuccessful. Rituximab is now recommended as the first-line treatment, being effective in ∼60% of cases (5–10% complete responses), with a response duration of 1–2 years. For refractory/relapsed cases, other options are rituximab plus fludarabine, bortezomib and eculizumab, although further studies are required to confirm their efficacy.

• Complement activation is a key mechanism in determining the clinical severity of AIHA, as observed in warm IgM, warm IgG + C, mixed and CAD with thermal range close to physiological temperatures, giving hints for future therapies (TNT003, C1-esterase inhibitors, compstatin Cp40 and TT30) aimed at specifically blocking the excessive activation of this powerful system.

• The use of more sensitive and non-routinely DAT is advisable in DAT-negative AIHAs, in particular when second-line therapies are required. Bone marrow biopsy and flow cytometry are strongly recommended to identify an underlying disease (lymphoproliferative, myeloproliferative or myelodysplastic), which can confound the clinical picture, puzzle the choice of the most appropriate therapy and invalidate its response. Bone marrow biopsy may be also advisable to evaluate the T- and NK-cell lymphocyte infiltrate, suggesting a T-specific modulating drug, such as cyclosporine or mycophenolate.

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