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Chapter 46 Autoimmune Hemolytic Anemia 661

Summary and Comment on the Experience on Warm Autoimmune Difficult Diagnosis of Secondary Warm Autoimmune Hemolytic Anemia
Hemolytic Anemia Antibodies in Adults of a Referral Center; Provided Antibodies
by Professor Marc Michel, Hôpital Henri Mondor, Creteil, France.
A 43-year-old woman was referred for an acute hemolytic anemia of
Roumier et al recently reported their experience on a series of 60 unknown etiology. She was a heavy smoker with no previous medical
adult patients diagnosed with WAIHA and seen at their institution over history. She started complaining of unusual fatigue and shortness of
a 10-year period (2001–2011). This analysis provides new insights breath in absence of overt bleeding 2 weeks before being admitted
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into the management and outcome of WAIHAs in the rituximab era in into another hospital. On clinical examination, she was pale with a
comparison with data from a previous series of 72 patients from their mild jaundice, her blood pressure and temperature were normal.
center seen before the year 2000. A mild hepatomegaly with splenomegaly was found with no other
Compared with the previous series, the major findings of this recent abnormalities. Upon admission, her Hb level was 4.2 g/dL with a
study were the following: MCV of 125 fL. The reticulocytes count was 603 × 109/L, platelet and
1) The rate of secondary cases of WAIHAs in adults has increased leukocytes counts were normal. Numerous spherocytes were found
beyond 50% now that an extensive workup including more on the blood smear with no other morphological abnormalities (see
systematically lymphocyte immunophenotyping in peripheral Fig. 46.2). The LDH level was 2866 UI/L (upper limit of the normal
blood and a CT-scan of the chest and abdomen is performed in value = 250 U/L); total bilirubin was 62 µmol/L (normal <30 µmol/L)
the absence of any obvious underlying disorder. with otherwise normal liver tests. Haptoglobin level was undetectable.
2) B-cell lymphoma represents the first cause of secondary WAIHA, The DAT with an anti-IgG and anti C3d was negative on two separate
especially in patients aged over 50 years, and in the absence of occasions. Glucose-6-phosphate dehydrogenase and pyruvate kinases
clonal disease or primary immunodeficiency, 10% of the patients blood levels were within the normal range and the search of a parox-
had some features of “unclassified lymphoproliferation” (see ysmal nocturnal hemoglobinuria clone was negative. The patient was
Fig. 46.2) that will need to be better characterized in the future transfused and then referred to our center.
3) The overall prognosis and outcome of adult WAIHA has Upon admission, a new DAT with an anti-IgA immunoglobulin was
significantly improved over the last decade (mortality rate was performed, which was found to be strongly positive. There was no
8% in the recent series compared with 18% in the older one) evidence of an underlying lymphoma on the CT scan of chest and
presumably in part thanks to the corticosteroid-sparing effect of abdomen and on the bone marrow biopsy. Hepatitis C serology was
rituximab increasingly used as a second- or third-line option. found positive as well as the PCR. The final diagnosis was WAIHAs
4) The initial response rate to corticosteroids was not significantly caused by an IgA autoantibody associated with chronic hepatitis C
different when patients with primary or secondary WAIHAs were virus (HCV). The patient initially achieved a response to high-dose
compared but corticosteroid dependency was observed in 100% prednisone but then had a relapse when the dose was tapered to
of the patients with an underlying lymphoma versus only 53% 20 mg/day. She did not respond to rituximab and mycophenolate
among patients without lymphoma (p = .007). mofetil but eventually achieved a complete remission after splenectomy
1 year after disease onset. This case illustrates: 1) spherocytes on the
blood smear are not specific of hereditary microspherocytosis and
can be found in AIHA; 2) before considering alternative diagnosis of
hereditary or acquired hemolytic anemia or retaining the diagnosis
Drug-Related Warm Autoimmune Hemolytic Anemia of DAT-negative AIHA, an extended DAT with the use of anti-IgA
antibodies must be performed; and 3) even in the absence of liver
Cessation of the drug may be effective in many cases, and further use abnormalities or past history of hepatitis, testing for the presence of an
of the drug should be avoided. Fludarabine-induced AIHA may be underlying HCV infection is valuable in the setting of WAIHA.
life threatening but responds to steroid therapy.

Treatment of Warm Autoimmune Hemolytic Anemia in infiltration. All patients should be advised to avoid cold exposure.
Congenital and Acquired Immune Deficiency States Drug treatment is required in only half of the patients. Treatment is
and Special Serologic Types initiated in symptomatic patients or when Hb levels drop below
9–10 g/dL. Because IgM-coated RBCs are mainly destroyed in the
liver, CAIHA does not respond to splenectomy and poorly to steroids.
The treatment of WAIHAs in patients with CVID is very similar to The most effective and best evaluated treatment is rituximab in a
that of those with primary WAHA. Additional regular prophylactic standard lymphoma dose. Two studies have provided similar results.
treatment with IgG concentrates reduces the risk of recurrence. In a prospective phase II study, 20 out of 27 patients responded, but
Splenectomy is effective, but the risk of serious infections is high. most responses (n = 19) were partial. The median response duration
In ALPS, treatment should be started with steroids and then was 11 months, but most patients responded to retreatment with
switched to MMF, but sirolimus has the highest efficacy in improving rituximab. A combination of rituximab and oral fludarabine induced
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not only AIHA but also lymphadenopathy. AIHA associated with higher ORRs (76%) with a longer duration (median: 66 months).
IgM hypergammaglobulinemia in Wiskott-Aldrich syndrome is an In a metaanalysis, the ORR for rituximab in CAD was 57% with a
indication for allogeneic stem cell transplantation. CR rate of 21%. 39
Patients with AIHA after allogeneic stem cell transplantation Given the role of complement in CAD, it is not surprising that
respond poorly to steroids but often do respond to rituximab. An the terminal complement inhibitor ecuzulimab is effective. 45,46 Recent
early switch to rituximab may be reasonable in these patients. AIHA results suggest that inhibition of the complement classical pathway
in drug-related severely immunosuppressed patients after transplanta- at the level of C1s results in remarkable responses and even CRs
tion of solid organs responds best to reduction of immune suppres- (TNT009). 47,48
sion. Patients with IgM WAIHAs respond poorly to steroids. These Positive results have been obtained with the proteasome inhibitor
patients are candidates for early rituximab treatment. The same is bortezomib in single rituximab-refractory patients. Preparation of
true for chronic AIHA caused by DL antibodies. patients with high-titer CAIHAs for surgery by cryofiltration may be
required in rare instances.
Treatment of Cold Autoimmune Hemolytic Anemia
Secondary Cold Autoimmune Hemolytic Anemia
Primary Chronic Cold Agglutinin Disease
In CAIHAs associated with lymphomas or solid tumors, treatment
Primary CAD is defined as a CAIHAs in patients with IgM-MGUS of the underlying disease by chemo(immuno)therapy or curative
or in lymphoma without overt clinical signs but with bone marrow resection results in good responses. Cases of infection-related CAIHAs