How I Treat

How I treat autoimmune hemolytic anemia

Ronald S. Go,1 Jeffrey L. Winters,2 and Neil E. Kay1
1
Division of Hematology, Department of Medicine, and 2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

Autoimmune hemolytic anemia (AIHA) is therapeutic approaches. To aid the clini- in the hope that this review may offer
an uncommon entity that presents diag- cian in AIHA management, we present guidance in regard to personalized ther-
nostic, prognostic, and therapeutic di- four vignettes that represent and highlight apy recommendations. A section is in-
lemmas despite being a well-recognized distinct clinical presentations with sepa- cluded for the diagnosis of suspected
entity for over 150 years. This is because rate diagnostic and therapeutic pathways AIHA with negative test results, a relative-
of significant differences in the rates of that we use in our clinical practice setting. ly infrequent but challenging situation, in
hemolysis and associated diseases and We also review the parameters present in order to assist in the overall evaluation

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because there is considerable clinical diagnostic testing that allow for prognos- spectrum for these patients. (Blood. 2017;
heterogeneity. In addition, there is a lack tic insight and present algorithms for 129(22):2971-2979)
of clinical trials required to refine and both diagnosis and treatment of the AIHA
update standardized and evidence-based patient in diverse situations. This is done

Introduction and history

The diagnosis, prognosis, and management of autoimmune hemolytic results. The “super-Coombs” test is an enhanced direct Coombs test
anemia (AIHA) continue to be challenging in current practice. This is that utilizes different methods to generate erythrocyte agglutination
related to an incomplete understanding of the pathophysiology of the (also reviewed in Table 4 below) and performed when the standard
disease process, complexity of initiating factors, and a lack of evidence- DAT result is negative.
based standardized therapies. There is no completely validated and The incidence of AIHA is considered uncommon, with prior
standard therapeutic approach to AIHA, because randomized clinical estimates of 1 to 3 in 100 000 population annually.6 AIHA affecting
trials are difficult to implement. children and adults and warm-reacting antibodies are the primary
Key historical events of AIHA include original descriptions of an pathogenic etiology in the majority of cases (;75% and ;90%,
AIHA-like disease in the 19th century and subsequently more defin- respectively).7,8 AIHA can be subdivided into warm- or cold-mediated
itive descriptions in the seminal publications of J. Donath and K. L and disease based on the thermal optimum used to detect anti–erythrocyte
steiner in the early 20th century.1-4 The direct antiglobulin test (DAT) antibodies. Primary AIHA comprises ;50% of cases, while secondary
was described by Robin Coombs and A. Mourant in 1945 and is a AIHA is usually associated with B-cell malignancies, autoimmune
laboratory-based assay still of great utility in the diagnosis of AIHA.5 diseases, or drugs. Primary (idiopathic) AIHA occurs when no disease
A positive DAT result, along with no other obvious cause of is clearly associated with the hemolysis, whereas secondary AIHA
hemolysis, is the defining clinical signature of AIHA. Antibodies occurs when hemolytic anemia is directly associated with another
directed against self-erythrocytes capable of induction of hemolysis at disease or drug believed to induce or promote the hemolysis. The
excessive or uncompensated rates result in an entity known as AIHA. progression of events that need to be dealt with in the management
These antibodies are usually immunoglobulin G (IgG) in nature, of AIHA includes using the appropriate methodologies for diagnos-
capable of fixing complement, and are detected by the DAT. The DAT ing AIHA, defining whether AHIA is primary or secondary in type,
is based on specific antibodies to IgG and/or C3d (fragment of the and identifying the most effective treatment for a given patient.9
third component of complement) capable of binding to these
components on the erythrocyte surface. If the latter molecules are
present in sufficient quantity on the erythrocyte membrane, the
result is a visible agglutination by cross-linking erythrocytes. DAT Serology that matters in warm AIHA (WAIHA)
techniques that enhance the sensitivity of this test beyond visual and cold agglutinin disease (CAD) evaluation
agglutination have been developed but are not routinely used. If more
commonly employed, these enhanced tests would increase the The essence of AIHA is that it is caused by the increased destruction of
detection of autoantibodies but are likely to lead to questions about erythrocytes by anti–erythrocyte autoantibodies. This can occur with or
their exact relationship to clinically important disease. These tests are without complement fixation and activation. Here is a primer for the
important in the setting of DAT-negative AIHA, an uncommon form clinician to aid in the fundamental understanding of immune mediators
of AIHA (see case 4). In contrast to the DAT, the indirect antiglobulin in AIHA, diagnosis, and prognostic risk.
(indirect Coombs) test is used to detect erythrocyte antibodies in Advances in understanding the pathophysiology of AIHA and
patient serum. This is done by incubating patient serum with a panel of how to use anti–CD20 antibodies with or without immunosup-
erythrocytes of known antigens and observing whether agglutination pressive agents has augmented treatment approaches.

Submitted 28 November 2016; accepted 21 March 2017. Prepublished online © 2017 by The American Society of Hematology
as Blood First Edition paper, 30 March 2017; DOI 10.1182/blood-2016-11-
693689.

BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22 2971

2972 GO et al BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22

Figure 1 shows the pattern of antibodies and complement that are How do we use glucocorticoids?
typically found on erythrocyte membranes in warm and CAD
While glucocorticoids are considered the first-line treatment in
AIHA.10-13 It features the most well-characterized erythrocyte
antigens involved in AIHA and the more typical diseases or drugs WAIHA, this was empirically derived. Mechanisms of actions in-
associated with specific AIHA subtypes. These autoantibodies can clude suppression of autoantibody production, reduction in auto-
be of IgG, IgM, or IgA isotypes, but most commonly, the antibody antibody affinity, and decreased destruction of erythrocytes by splenic
is an IgG antibody in WAIHA and an IgM antibody in CAD. The macrophages, perhaps by diminished expression of Fcg receptors.21,22
IgA isotype is much less commonly involved in AIHA but may The first-ever randomized trial of newly diagnosed AIHA compared
cause severe hemolysis.14,15 The ability of the anti–erythrocyte high-dose prednisone (1.5 mg/kg per day 3 2 weeks, then tapered over
antibody to bind to the erythrocyte antigen at specific temperatures 8-12 weeks), with or without rituximab, found that 50% of patients
is fundamental to the diagnosis in terms of whether it is designated in the prednisone-only group achieved either a complete response (CR)
as warm (reacts maximally at 37°C) or cold (reacts maximally at or partial response (PR) at 3 months. However, nearly half of the
,4°C) AIHA. The pathologic and clinical features of AIHA relate responders relapsed within a year. This study was limited by small
to the autoantibody class, thermal amplitude, and their efficiency in sample size (N 5 64) and did not report the proportion of patients
needing second-line treatment after relapse. The rituximab arm had

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activating complement. It is known that the broader the thermal
higher rates of CR at 12 months (75% vs 36%) and relapse-free survival
amplitude, the worse the rate of hemolysis for IgM cold agglutinins.
With initiation of therapy, it is best to monitor restoration of the at 36 months (70% vs 45%).23 A prospective registry study of 308
hemoglobin and reticulocyte levels over the first several weeks of patients showed a higher prednisone-based response rate of 80%. Half
therapy. Monitoring the DAT is routine, but even if the result did not require subsequent treatment after a median follow-up of
remains positive, this may not reflect a lack of disease control. The 33 months.24 The optimal starting dose and taper schedule of prednisone
extent of hemolysis must be matched by a robust marrow-based are unknown, although most reports and experts use starting doses of
erythrocyte production rate but may be insufficient.16,17 Insuffi- 1.0 to 1.5 mg/kg per day or a flat dose of 60 to 100 mg daily.25-27 The
cient reticulocytosis may occur in children and in adults with very starting dose is maintained for at least 2 weeks and until achievement
severe hemolysis. Recognition of this phenomenon has generated of hemoglobin .12 g/dL. Thereafter, we taper the prednisone by 20 mg
data indicating that the use of erythropoietin may be useful in every week until a dose of 20 mg daily is reached, followed by a slower
taper over 4 to 8 weeks. We monitor hemoglobin levels on a weekly
managing situations like this and refractory AIHA.18
basis until the tapering process is complete. Thereafter, less frequent
testing is needed. The success of high-dose dexamethasone (40 mg
daily for 4 days) in the initial treatment of immune thrombocytopenia
makes an attractive alternative option in the treatment of WAIHA,
Case 1: idiopathic WAIHA although further studies are needed.28 One study showed its efficacy
in the setting of refractory AIHA.29 Because chronic hemolysis
A 68-year-old previously healthy woman presented with new-onset may potentially lead to folate deficiency due to increased utilization,
fatigue. Physical examination was remarkable only for mild pallor. it is customary to supplement with 1 mg folic acid daily when
Laboratory test results (with reference ranges provided in brackets) glucocorticoid is started.
were significant for hemoglobin (9.3 g/dL [12.0-15.5]), mean cell
volume (MCV; 89.7 fL [81.6-98.3]), absolute reticulocyte count
What is the value of splenectomy?
(119 3 109/L [38.1-112.6]), haptoglobin (,14 mg/dL [30-200]),
lactate dehydrogenase (LDH; 267 U/L [122-222]), total bilirubin Splenectomy is effective but has never been compared with other
(0.8 mg/dL [0.1-1]), and blood smear showing polychromasia. The treatments in the second-line setting. The response rate of splenectomy
DAT showed 21 anti-IgG and weakly positive anti-C3. in unselected patients is ;60% to 90%, and approximately one-third
will relapse, mostly within 1 to 2 months.24,30,31 Patients without an
Should we routinely evaluate for an underlying underlying autoimmune disease or hematologic malignancy are twice
lymphoid malignancy? as likely to respond as those with such conditions (82% vs 19%
complete response).32 Although rituximab has increasingly superseded
Contemporary series composed of unselected patients with WAIHA splenectomy in recent retrospective studies and may be primary second
are scarce. A recent single-institutional study (N 5 60) showed that line for some centers,33 we still consider splenectomy as the primary
an underlying condition could be found in 48% of patients at or second-line option in idiopathic AIHA. In one study of 52 patients with
preceding the diagnosis and in another 8% subsequently. The most AIHA, 64% were in unmaintained remission after a mean follow-up of
common conditions were lymphoma or undefined lymphoprolifer- 33 months. Relapse patterns were not reported separately for idiopathic
ative disorder (54%) and autoimmune diseases (27%).19 Another and secondary AIHAs.30 For those with underlying medical conditions,
report (N 5 107) studied warm and cold AIHA cases initially alternative treatments such as rituximab and disease-specific therapies
considered idiopathic or associated with autoimmune disorders and may be a better next option. It is absolutely essential to vaccinate against
found that 18% of patients developed lymphoma at a median of encapsulated bacterial organisms at least 14 days prior to (preferable) or
27 months.20 In both studies, evaluation for lymphoma was not at least 14 days after splenectomy to maximize immunity.34
routinely performed at the time of AIHA diagnosis. Therefore, the
prevalence of lymphoma is likely to be underestimated. It is How do we treat subsequent relapse or refractory disease?
reasonable to consider evaluating for lymphoid malignancies,
including a computed tomographic scan of the chest, abdomen, and With no standard definition for treatment responses reflecting refractory
pelvis, as well as bone marrow biopsy in patients with newly or relapsed AIHA, the definition proposed by Barcellini et al is useful.35
diagnosed AIHA. Discovery of such malignancies upfront may We consider a subsequent line of treatment in the following scenarios:
open the option of non–glucocorticoid-based therapies, improve (1) requirement of .20 mg of prednisone daily (or equivalent
the chance of response, and minimize relapses. corticosteroid) to maintain hemolysis control; (2) clinically significant
BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22 HOW I TREAT AUTOIMMUNE HEMOLYTIC ANEMIA 2973

AIHA SEROLOGY AND CLINICAL CAUSES

* DAT TEST ANTIGEN

TYPE OF AIHA CAUSES
RESULT INVOLVED

Idiopathic;
autoimmune
IgG+ and C3- Warm Rh ± drug
disease; drug;
lymphoma

Idiopathic;

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Glycophorin ± autoimmune
IgG+ and C3+ Warm
drug disease; drug;
lymphoma

IgM monoclonal gammopathy;

Cold Agglutinin Waldenström
I- or i- antigen
Disease macroglobulinemia;
Mycoplasma pneumonia;

Paroxysmal Cold Viral infection;

IgG- and C3+ P-antigen
Hemoglobinuria lymphoma

Idiopathic;
Glycophorin ± autoimmune
Warm
drug disease; drug;
lymphoma

Figure 1. Direct antiglobulin test serology and clinical aspects. Shown are the spectrum of DAT serologic findings, autoimmune hemolytic classifications, antigen
specificity, and medical/drug associations.10,11 Drugs most commonly implicated11-13,20 in drug-induced autoimmune hemolytic anemia are b lactam antibiotics (penicillin,
ceftriaxone, cefotetan, and piperacillin), nonsteroidal anti-inflammatory drugs (tolmetin, sulindac, and diclofenac), quinine, purine nucleoside analogs (fludarabine and
cladribine), and platinums (cisplatin and oxaliplatin).12,13

relapse (hemoglobin , 11g/dL or symptomatic anemia with ongoing In our experience using noncorticosteroid immunosuppressive
evidence of hemolysis); or (3) intolerance to a currently effective agents, the response may take months to be evident. Therefore, it
treatment. If hemolysis continues that is well compensated after is reasonable continue treatment of at least 8 to 12 weeks, especially
prednisone tapering, starting a second-line treatment may not be if the hemolysis rate is stable during treatment. A recent review
necessary. Similarly, DAT negativity is not essential with controlled article has more in-depth discussions of the individual treatment
hemolysis. The more commonly used treatments along with their options for relapsed or refractory disease.26
corresponding dosing schedules are displayed in Table 1.36-42 Patterns
of care studies are not available, but single-agent rituximab is perhaps
the most commonly used treatment in this setting and is our first
choice after splenectomy relapse. In a meta-analysis of 21 studies that Case 2: WAIHA associated with chronic
investigated rituximab, the overall response (OR) and CR rates were lymphocytic leukemia (CLL)
79% and 42%, respectively. The OR was similar regardless of whether
it was idiopathic or secondary AIHA (67% vs 72%).43 In studies with A 62-year old male with a history of CLL presented with profound
.3 years of follow-up, the relapse rate was ;50%. However, most fatigue. He was severely anemic with hemoglobin of 5.8 g/dL.
patients responded to rituximab retreatment.19,44 Additional laboratory test results (with reference ranges in parentheses)
Information about response rates and their duration for less used included MCV 93.5 fL, white cell count 4.0 3 109/L (3.5-10.5), platelet
drugs often varied and were frequently not reported. Many of these count 50 3 109/L (150-450), absolute lymphocyte count 1.6 3 109/L
treatments were added to corticosteroids at relapse. It is impossible (0.9-2.9), absolute reticulocyte count 10 3 109/L, haptoglobin
to determine the comparative efficacy of these treatments. We ,14 mg/dL, LDH 420 U/L, total bilirubin 2.0 mg/dL, indirect bilirubin
caution the treatment outcomes in Table 1 may look more optimistic 1.5 mg/dL (,1.0), and blood smear showing polychromasia. DAT
due to reporting bias and small study sample sizes. The choice of showed 21 anti-IgG and no anti-C3. He was treated a year ago with
treatment beyond rituximab will depend on the physician’s clinical a fludarabine/cyclophosphamide/rituximab combination regimen and
judgment, the patient’s preference, and the drug’s side effect profile. achieved a PR.
2974 GO et al BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22

Table 1. Pharmacologic treatment options for relapsed or refractory warm autoimmune hemolytic anemia from a case series
Median time to Median response Relapse rate
Treatment Initial dose(s) OR, % response (range) duration (range) (at 1-2 y), % Comments Reference
Azathioprine 2-4 mg/kg orally once a day 50-70 NA 11 mo (4-36) 60 N 5 9-31 19, 24, 36, 37
Cyclophosphamide 1-2 mg/kg orally once a day; or 50-70 NA 11 mo (4-36) 50 N 5 7-40 19, 24, 26, 37
(low dose) 50-150 mg orally once a day
Cyclophosphamide 50 mg/kg IV days 1-4 with mesna 100 3 wk; 82% at 15 mo (4-29) 0 For the 50 mg/kg dose, 40% 38, 39
(high dose) and granulocyte colony 4 mo hospitalization due to
stimulating factor rescue; or complications (N 5 9-17)
1000 mg IV every 4 wk 3 4
Cyclosporine 2.5 mg/kg orally twice a day 60 NA 11 mo (4-36) NA Maintain serum level 24
200-400 ng/mL (N 5 12)
Danazol 200 mg orally 3-4 times daily 60-80 NA 18 mo (7-77) 30-75 Maintenance dose 8, 40, 41
200-400 mg/day (N 5 15-22)
Mycophenolate 500-1000 mg orally twice a day 25-70 5 mo (1-9) 11 mo (4-36) NA N 5 3-4 19, 24, 42

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Rituximab 375 mg/m2 IV every week 3 4; or 70-90 2 wk (1-12) 20 mo (9-60) 20-50 N 5 25-74 19, 24, 44
100 mg IV every week 3 2-4

NA, not available.

When is erythrocyte transfusion indicated or contraindicated, there is no absolute contraindication to erythrocyte transfusion, as it
and what needs to be considered when transfusing a patient? remains a safe procedure.
Consideration of erythrocyte transfusion for hemodynamically
Do we treat the CLL or AIHA or both?
stable patients with a hemoglobin of ,7 g/dL is based on the AABB
guidelines.45 This restrictive strategy applies to the relatively We first determine whether there is an indication for the treatment
asymptomatic patient. For patients who are experiencing cardiopul- of CLL based on the International Workshop on CLL guidelines for
monary symptoms due to anemia, erythrocyte transfusion should not active disease.46 If chemotherapy is indicated, then any of the nonpurine
be withheld regardless of hemoglobin level. Because the major nucleoside analog containing chemoimmunotherapy combinations or
erythrocyte antigenic targets of the autoantibodies (Rh, Rh-related, ibrutinib may be used, since they are not known to be associated with
band 3, or glycophorin) are nearly universally present in humans,27 or cause hemolysis.47 The AIHA generally responds in parallel to CLL
special compatibility test procedures are necessary to rule out the therapy. Otherwise, the treatment is similar to what is used for AIHA in
presence of an alloantibody and proper crossmatching. These tests the nonmalignant setting.
include removing the autoantibody from the patient’s serum, leaving
behind any alloantibodies by utilizing either the patient’s (autolo- How commonly does AIHA occur during fludarabine treatment?
gous) red blood cells or selected sets of donor red blood cells
of known antigen type to adsorb the autoantibody. The adsorbed The incidence of AIHA among previously untreated patients receiving
serum (adsorbate) is then used to identify any potential allogeneic nonpurine nucleoside analog based treatment is ;2%.48 This contrasts
antibodies by reacting it against panels of red blood cells of known with the ;6% incidence among those receiving fludarabine-based
antigen type (antibody screen) and to perform crossmatching to therapy.49-51 In the latter group, the majority of cases occur during the
identify compatible erythrocytes. In severe anemia, there may be first 3 treatment cycles, although AIHA can occur at any time during
insufficient autologous erythrocytes to perform an autologous treatment and reoccur after rechallenge. Hemolytic episodes can be
adsorption. To enhance the safety of transfused erythrocytes, it severe enough to require transfusion, and fatalities have been
is possible to use erythrocytes phenotypically matched with the reported.52 One randomized trial showed that the combination
patient. This means determining the antigen profile of the patient’s of fludarabine and cyclophosphamide might have a lower incidence of
erythrocytes using typing sera for antigens toward common AIHA than fludarabine alone.50 However, this was not supported by
alloantibodies. Antigen typing of the patient’s erythrocytes should other randomized trials.49,51 In another randomized trial, the incidence
be performed prior to transfusion or at least 3 months after the of AIHA was similar (;1%) among those who received fludarabine
patient’s last transfusion to avoid potential inaccurate typing. De- and cyclophosphamide with or without rituximab.53 Thus, we
termining the “molecular phenotype” of a patient in order to provide generally discontinue fludarabine-based therapies in the setting
antigen matched red blood cells is possible and can be used in of AIHA, especially when the hemolysis is severe. Purine nucle-
transfused patients. oside analogs such as pentostatin and cladribine are also associated
While phenotyping and providing phenotypically matched eryth- with AIHA and should be avoided.54,55 If further chemotherapy
rocytes reduces the risk of hemolysis due to alloantibodies “hiding is unnecessary, we use corticosteroids alone. If additional CLL
behind” an autoantibody, it does not eliminate it. More than 400 red treatment is needed, we prefer rituximab/cyclophosphamide/
cell antigens have been identified, and typing sera are available for a dexamethasone, bendamustine/rituximab, or novel signal inhibi-
minority. Molecular phenotyping may also fail to correctly determine a tors because of their safety in this setting.56-59 These 2 chemother-
patient’s antigen type because of gene silencing through mutations apy combination regimens have been shown to effectively treat
occurring outside of antigen coding regions. The presence of these steroid-refractory AIHA. In most (.80%) of the cases, there was
other methods means that immediate discussion with the blood bank sustained control of hemolysis and CLL.58,59 Among those who
personnel is necessary to avoid delays or miscommunication and allow were receiving AIHA treatment, the initiation of ibrutinib
for timely testing. It is expected that the transfused erythrocytes, even frequently allowed discontinuation of AIHA treatment within
if phenotypically matched, will have shorter half-lives. Nevertheless, 5 months.47
BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22 HOW I TREAT AUTOIMMUNE HEMOLYTIC ANEMIA 2975

Table 2. Pharmacologic treatment options for relapsed or refractory cold agglutinin disease from case series
Median time To Median response Relapse rate
Treatment Initial dose OR, % response (range) duration (range) (at 1-2 y), % Comments Reference
Chlorambucil 4-20 mg orally once a day 16-46 NA 11 mo NA Included newly diagnosed 64, 65
Cyclophosphamide 50-150 mg orally once a day and previously treated
patients (N 5 19-37)
Rituximab 375 mg/m2 IV every week 3 4 wk 45-54 1.5 mo (1-2) 10 mo (8-27) 50-83 Included newly diagnosed 64, 67, 68
and previously treated
patients (N 5 20-32)
Rituximab 1 prednisone Rituximab: 100 mg IV every 56 2 wk NA 33 Included newly diagnosed 35
week 3 4 wk; Prednisone: and previously treated
1 mg/kg per day orally 3 30 d, patients (N 5 19)
then taper
Rituximab 1 fludarabine Rituximab: 375 mg/m2 IV every 76 4 mo .66 mo (3-66) 23 Grade 3-4 hematologic 73
4 wk; Fludarabine: 40 mg/m2 toxicities in 41% (N 5 29)

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orally on days 1-5 every 4 wk;
both 3 4 cycles

NA, not available.

Are any of the recently approved CLL drugs associated electrophoresis showed a small, unquantifiable amount of IgMk
with AIHA? monoclonal protein, while Mycoplasma pneumoniae serology was
consistent with past exposure. Cold agglutinin titer was .512. Physical
Five drugs have been recently approved for use in CLL: ibrutinib, examination was unremarkable.
idelalisib, obinutuzumab, ofatumumab, and venetoclax. There is no
evidence from randomized trials to suggest that any of these agents
What should be the extent of workup for a hematologic
increases the absolute risk of AIHA.48,60-62 There is a flare phenomenon
malignancy at the time of diagnosis?
described among patients with preexisting immune cytopenias treated
with ibrutinib.57 Immune cytopenia may exacerbate shortly after In half of the cases, an autoimmune condition or infection
starting ibrutinib (within a median of 3 weeks and ranging from 2 to (M pneumoniae or Epstein-Barr virus) are identified as potential
8 weeks). The flare episode can be managed by continuation of precipitating factors.63 In the remainder, CAD is commonly associated
ibrutinib with or without the addition of corticosteroids.57 with an underlying clonal B-cell disorder similar to WAIHA. In a recent
series of non–infection-related CAD patients (N 5 89), 34% were
found to have a B-cell lymphoma, and another 47% had monoclonal
gammopathy of undetermined significance.64 The predominant mono-
Case 3: CAD clonal protein was IgMk (95%), while the rest was either IgGl or
IgAl.65 Therefore, a routine evaluation for non-Hodgkin lymphoma
A 54-year-old man with acute bronchitis was treated with azithromycin that includes bone marrow biopsy and body computed tomographic
with resolution of respiratory symptoms. Because of continued fatigue, scan should be considered when there is no obvious infection.
laboratory tests were performed, which showed hemoglobin 11.4 g/dL,
MCV 100 fL, absolute reticulocyte count 266 3 109/L, haptoglobin Who should we treat?
,14 mg/dL, LDH 295 U/L, total bilirubin 1.3 mg/dL, and indirect
bilirubin 1.0 mg/dL; the blood smear showed erythrocyte agglutina- Supportive measures aimed at avoiding cold exposures apply to all
tion. DAT showed weak1 anti-IgG and 31 anti-C3. Serum protein patients regardless of symptoms. Day-to-day practices include ade-
quate clothing for cold weather, keeping indoor thermostat at higher set
points, and avoidance of icy drinks and cold showers. If the patient is
Table 3. Mechanisms involved in DAT-negative WAIHA
admitted due to a medical event or for surgery, the application of body-
1. Erythrocyte-bound antibody below the limit of detection of standard DAT warming blankets and prewarming of IV fluids and blood products may
Erythrocytes from healthy individuals have up to 35 molecules of IgG bound to minimize the exacerbation of the hemolysis. We consider systemic
their surface.
treatment when there are substantial or disabling signs or symptoms
Standard DAT can detect .300-500 bound IgG molecules.
despite supportive measures. These include cold-induced manifesta-
WAIHA can occur with as few as 70-434 bound IgG molecules.
2. Low-affinity IgG antibodies
tions such as acrocyanosis or Raynaud phenomenon and clinical
Loosely bound antibodies are dislodged during the washing of erythrocytes or sequelae of anemia and hemolysis. CAD associated with infections is
when samples are left standing at room temperature. usually self-limited and generally does not require treatment.66 It
3. IgA antibodies is necessary to treat the underlying lymphoproliferative disorder if this
IgA antibodies may trigger phagocytosis and antibody-dependent cell cytotoxicity, is present.
resulting in hemolysis.
Standard anti–human globulin reagents do not have anti-IgA activity, as most What is the efficacy of rituximab?
polyspecific reagents contain a mixture of monoclonal anti-IgG and anti-C3d.
4. Warm-reacting IgM and monomeric IgM antibodies Despite the lack of randomized trials, single-agent rituximab is
IgM antibodies reacting at warm temperatures and monomeric IgM may not fix currently considered the first-line systemic therapy for CAD due to
complement. its superior efficacy and tolerability. Two relatively larger prospective
Standard anti–human globulin reagents do not detect IgM. However, these
studies that included newly diagnosed and previously treated patients
antibodies will detect C3d if the IgM antibody fixes complement.
(N 5 20 and N 5 27) have shown ORs ranging from 45% to 54% with
2976 GO et al BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22

Table 4. Enhanced DATs

Name Description DAT-negative WAIHA detected
Column agglutination Erythrocytes are placed on a column of beads suspended in diluent containing Low-affinity autoantibodies
anti–human globulin reagent and centrifuged.
Agglutination of antibody-coated erythrocytes results in cells failing to migrate in the
bottom of the column.
No cell washing is required, as serum/plasma is retained on top of the column.
4°C Low-ionic-strength Erythrocytes are washed with cold, low-ionic-strength saline to avoid removal of Low-affinity autoantibodies
saline wash low-affinity antibodies.
Polybrene Polybrene induces aggregation of erythrocytes, which are dispersed by sodium citrate. Erythrocyte-bound antibody below limit of
If antibody is present, erythrocytes will not disperse. detection of standard DAT
Flow cytometry Erythrocytes incubated with anti–human globulin reagent are tagged with fluorescence Erythrocyte-bound antibody below limit of
and examined by flow cytometry. detection of standard DAT
Anti–human globulin reagents to IgG, IgA, and IgM are used. IgA antibody
Erythrocyte-bound IgM and monomeric IgM

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antibody
IgA Anti-IgA is used instead of anti-IgG and anti-C3d. IgA antibody
IgM Anti-IgM is used instead of anti-IgG and anti-C3d. IgM warm antibody and monomeric IgM

median times to response between 1 and 2 months and median is generally lower. Treatments reported to have nearly no response are
response durations of 8 to 11 months. However, CRs were uncommon azathioprine and cladribine.65,74 Treatments reported to be effective
(,5%). The responses were similar regardless of the presence or but published as single case reports are bortezomib, eculizumab,
absence of an underlying lymphoid malignancy.67 Another pro- rituximab/bendamustine, rituximab/cyclophosphamide, and rituximab/
spective study (N 5 19) used a combination of rituximab and fludarabine/cyclophosphamide.59,75-80
prednisone and achieved a relatively shorter median time to response
(2 weeks), more CRs (56%), and fewer relapses (33% at 12 months),
suggesting a potential additive effect.35 Both standard-dose
(375 mg/m2 IV weekly 3 4) and low-dose (100 mg fixed dose IV
Case 4: DAT-negative AIHA
weekly 3 4) rituximab were effective.35,67,68
A 50-year-old male presented with a 2-week history of fatigue and
Do corticosteroids work? jaundice. He denied alcohol use, risk factors for viral hepatitis, recent
travel, and toxin exposure, and he was not taking any medication.
Older studies showed poor responses to corticosteroids (,15%
Physical examination showed icteric sclerae and hepatosplenomegaly.
OR),65,69 but recent studies suggest that corticosteroids are still
Further evaluation showed hemoglobin 6.0 g/dL, absolute reticulocyte
commonly used and have higher response rates. In one study,
count 272 3 109/L, platelet count 245 3 109/L, LDH 1000 U/L,
corticosteroids were used in 24 of 89 patients (27%), mostly (81%) as
haptoglobin ,14 mg/dL, total bilirubin 6.3 mg/dL, indirect bilirubin
first-line treatment, and produced an OR of 36%. One-third of patients
4.7 mg/dL, 2 negative DAT results, no paroxysmal hemoglobinuria
did not require additional therapy after long-term follow-up.64
clone, and blood smear with marked spherocytosis. Bone marrow
Another study (N 5 64) of patients receiving corticosteroids reported
biopsy specimen demonstrated erythroid hyperplasia. Due to worsen-
an OR of 69% (mostly PRs). Many patients had to be maintained
ing symptomatic anemia, he was transfused with 4 U erythrocytes,
on corticosteroids at higher doses compared with WAIHA patients.24
which raised the hemoglobin to 10.0 g/dL, but within 24 hours,
In one of these two recent large series, half of the patients had
hemoglobin declined to 7.5 g/dL. Because of the high index of
predominantly IgG cold agglutinin.64 Reports suggest long-term
suspicion for WAIHA, enhanced DATs were performed and detected
efficacy of corticosteroids in this latter subgroup.70,71
a low-affinity IgG antibody.
What is the value of splenectomy?
How common is DAT-negative WAIHA?
Splenectomy is generally not recommended as a treatment in CAD,
as erythrocyte destruction is known to primarily occur in the liver.72 A total of 3% to 11% of patients with hemolytic anemia clinically
In the 3 largest series of primary CAD reported in recent years (total consistent with WAIHA will have a negative DAT result.81,82
N 5 259), only 11 patients (4.2%) were treated with splenectomy, A negative test result, considered critical for the diagnosis of WAIHA,
although, surprisingly, 3 (27.3%) responded with a response may lead physicians to reject the diagnosis, resulting in additional
duration between 5 and 15 months.24,64,65 The antibody specificities patient evaluation and delays in treatment. It is therefore important to
of the DAT in these patients were not reported. There are anecdotal recognize the existence of DAT-negative WAIHA. The most common
reports that some patients with predominantly IgG cold agglutinin “cause” of DAT-negative WAIHA is technical. Approximately 10% to
may achieve a durable response to splenectomy.70 50% of patients with DAT-negative WAIHA will have a positive
standard DAT result using anti-IgG and anti-C3d reagents retested at
How do we treat subsequent relapse or refractory disease? immunohematology reference laboratories.81,83,84 If suspicion of
WAIHA remains high, DAT should be repeated, preferably by an
Data on the efficacy of alternative systemic treatments are limited immunohematology reference laboratory. The presenting clinical
for CAD. A summary of case treatment series with reported efficacy features and treatment responses of patients with DAT-negative
in CAD are shown in Table 2.73 While most immunosuppressive or WAIHA are similar to those of patients with DAT-positive
cytotoxic agents used in WAIHA have been tested in CAD, the efficacy WAIHA.85
BLOOD, 1 JUNE 2017 x VOLUME 129, NUMBER 22 HOW I TREAT AUTOIMMUNE HEMOLYTIC ANEMIA 2977

How do we test for DAT-negative AIHA? relapsed setting. Novel strategic therapies can be devised based on
known pathophysiology that would improve on the decrease or
The identified mechanisms by which erythrocyte antibody escapes
removal of autoantibody production and/or reduce the phagocytosis
recognition by standard DAT are listed in Table 3.81,82 There are of antibody/complement-coated erythrocytes. There is an ongoing
several “enhanced” DATs that can be performed to detect one or phase 2 trial (NCT02612558) evaluating the use of a syk inhibitor,
more of the described mechanisms. The more common enhanced fostamatinib, in the therapy of refractory AIHA, a phase 3 trial of
DATs are shown in Table 4.81,82 No single enhanced DAT will rituximab in upfront therapy of AIHA (NCT01181154), and a completed
detect all potential hemolytic mechanisms requiring a panel of tests. trial of low-dose rituximab plus prednisone (NCT01345708 and
NCT00309881). Given the role of interaction of IgG with the Fc
Conclusion and challenges
g receptor [FcgR] or the neonatal Fc receptor [FcRn] in autoimmune
The etiology of AIHA remains incompletely understood; however, the disease, there is growing interest in blockade or modulation of these
mechanisms of erythrocyte destruction and the clinical complications latter receptors with various formulations of intravenous immuno-
that accompany this disorder are well defined. The clinical heteroge- globulin.86 These trials and investigations show that novel agents
neity of AIHA requires the clinician clearly define the nature of the are being tested in AIHA to enhance our effective therapeutic

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disorder for each patient. In this article, we also emphasized approaches repertoire and should expand our therapeutic repertoire in the
to AIHA where the DAT result is negative. The determination that coming years.
the AIHA is warm or cold mediated does give significant insight into
the potential clinical course and its management. We have provided the
rationale and evidence basis for certain treatments and their relative
hierarchy for use in the subtypes of AIHA. We have also highlighted Authorship
the need to look for associated diseases, as their management may aid
in AIHA therapy. Contribution: R.S.G., J.L.W., and N.E.K. designed research, per-
The usual options for treatment of warm-mediated AIHA with formed research, analyzed data, and wrote the paper.
steroids with or without rituximab and or splenectomy can be Conflict-of-interest disclosure: The authors declare no competing
considered to be standard practice and are very helpful in ;80% of financial interests.
cases. However, the upfront management of CAD is typically less ORCID profiles: R.S.G., 0000-0002-8284-3495; J.L.W., 0000-
successful and remains a challenge. Tables 1 and 2 list the treatment 0001-8654-3732; N.E.K., 0000-0002-5951-5055.
options for relapsed or refractory warm- and cold-mediated AIHA, Correspondence: Neil E. Kay, Division of Hematology, Mayo
respectively. There is no clear consensus on the sequence or timing of Clinic, 200 First St SW, Rochester, MN 55905; e-mail: kay.neil@
these agents, so additional studies are needed to improve efficacy in the mayo.edu.

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