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Treatment of Cold Agglutinin Disease

December 6, 2021

December 2021

Sigbjørn Berentsen, MD, PhD, discusses the diagnosis and management of cold agglutinin disease, a rare subtype of autoimmune hemolytic anemia. This material is repurposed from “How I treat cold agglutinin disease,” published in the March 11, 2021, edition of Blood.

Fast Facts

  • Appropriate diagnostic workup is essential for optimal therapy and must include monospecific DAT, CA titer, and relevant examinations for underlying bone marrow LPD.
  • Treatment for CAD is not always indicated. Treatment recommendations must be based on nonrandomized studies and will be influenced by personal experience.
  • Corticosteroids should not be used to treat CAD. B cell–directed therapies are temporary and often highly efficacious, and should be considered as the first choice in most cases.
  • Sutimlimab is an emerging second-line option and may even be considered in the first line for initial treatment of severely anemic patients without disabling ischemic symptoms.
  • Bortezomib-based regimens or, in highly selected cases, rituximab plus fludarabine will be alternatives in the second or third line.

Cold agglutinin disease (CAD) has a prevalence of 5 to 20 cases per million and an incidence of 0.5 to 1.9 cases per million per year, showing considerable variation with climate. CAD accounts for 15% to 30% of autoimmune hemolytic anemias (AIHAs). CAD is defined as an AIHA with a monospecific direct antiglobulin test (DAT) strongly positive for C3d (and negative or weakly positive for immunoglobulin G [IgG]) and a cold agglutinin (CA) titer of 64 or greater at 4°C.

Approximately one-quarter of patients with CAD have severe anemia, defined as hemoglobin (Hb) <8.0 g/dL. At least in cool climates, most patients also have ischemic symptoms, such as acrocyanosis or Raynaud-like phenomena, resulting from agglutination of erythrocytes in the acral circulation. Complement-driven exacerbation of hemolysis is common during febrile infections and other conditions with acute-phase reaction. Estimates on transfusion dependency show considerable variation; unselected series indicate that approximately 40% of patients have been transfused. Fatigue is a well-known symptom of unknown frequency and can be attributed to complement activation, as well as the eponymous anemia itself.

The past two decades have seen great progress in the development of new treatment options based on prospective trials. Each of the two major steps in the pathogenesis of CAD – clonal B-cell lymphoproliferation and complement-mediated hemolysis – constitutes a logical and promising target of therapy. This article reviews strategies for the diagnosis and management of this rare disease.

Diagnostic Workup

The importance of a targeted history and clinical examination should be emphasized; this will identify the frequently occurring clinical features and contribute to the exclusion of clinically overt lymphoma (known as secondary cold agglutinin syndrome). The diagnosis of hemolytic anemia is based on Hb level and markers of hemolysis, such as bilirubin, lactate dehydrogenase, and haptoglobin. Absolute reticulocyte counts will usually, but not always, be elevated.

A monospecific (extended) DAT must be performed to confirm autoimmune pathogenesis and recognize complement activation. The typical DAT pattern in CAD is a strongly positive test for C3 (usually C3d) only, but in up to 20% of patients, DAT is weakly positive for IgG as well. Because DAT can be positive for C3 only, even in IgM-mediated warm AIHA, CA titration is mandatory for diagnosis (see FIGURE). The CA titer is typically ≥64 but often much higher. Determination of the thermal amplitude of the CA can be time-consuming and is not necessary in all patients in clinical practice, but it can be useful for ruling out clinically insignificant CAs when relevant.

FIGURE. Algorithm for the Diagnostic Workup and Management of Cold Agglutinin Disease

Counseling on thermol protection: All patients with confirmed CAD


In practice, we also routinely determine serum complement C3 and C4, although normal levels do not exclude CAD. Secondary CAS must be ruled out by clinical evaluation and, if required, appropriate imaging and relevant tests for specific infections. Computed tomography scans are unlikely to provide any additional information if there is no clinical suspicion of aggressive lymphoma or solid malignancy.

After establishing the CAD diagnosis, the presence of a CA-associated lymphoproliferative disorder (LPD) should be evaluated by serum protein electrophoresis (SPEP), immune fixation, immunoglobulin class quantification, and bone marrow biopsy. If histologic evidence of clonal LPD is found, a mutational analysis of MYD status should be included. Flow cytometry in a bone marrow aspirate should also be performed; this examination is not sensitive enough if performed in peripheral blood.

Recognition of the specific features of CA-associated LPD is not always easy, and the biopsy findings may be interpreted as lymphoplasmacytic lymphoma, marginal zone lymphoma, or another indolent lymphoma, even in some cases of primary CAD. Centralized biopsy assessment by a pathology department with relevant expertise has been shown to markedly facilitate the recognition of CA-associated LPD.

For CA titration and all immunoglobulin analyses, including SPEP and quantifications, it is critical to handle the blood samples as described in the TABLE. Failure to comply with this procedure will result in reduced sensitivity and inaccurate estimates.

Deciding to Start Treatment

Patients with mild anemia or compensated hemolysis and no clinical symptoms have not been shown to benefit from treatment. However, the restrictive attitude to drug therapy often found in the literature seems influenced by the poor efficacy of older therapies.

Today, it is reasonable to treat those with bothersome symptoms who can be expected to benefit from therapy (i.e., patients with symptomatic anemia or disabling Raynaud-like symptoms). Fatigue in the absence of significant anemia remains a more controversial indication, although there are emerging data on benefit.

All patients, including those for whom pharmacologic treatment is not indicated, should be counseled on thermal protection. Counseling physicians and nurses on this rare disease seems equally important.

Managing Thrombotic Risk

Registry-based studies of patients diagnosed with CAD by their hospitals have found an increased risk of thromboembolic events (TEs), with a relative risk up to 3.1 compared with matched controls.

Successful CAD-directed therapy seems to reduce the frequency of TEs, but there are no data to show any impact of treatment of asymptomatic patients on TE risk. As a reasonable preliminary conclusion, an assumed risk of TEs should not be considered an indication for CAD-directed therapy in patients with mild anemia or compensated hemolysis. Untreated patients with severe anemia or acute exacerbation, as well as those with additional risk factors, should probably receive prophylaxis with low-molecular-weight heparin or a direct oral anticoagulant.

Not all treatments used in warm AIHA are effective in CAD. Unfortunately, ineffective therapies are still prevalent worldwide. CAD should not be treated with corticosteroids, which result in remission in <20% of patients. In the few responders, unacceptably high maintenance doses are often required for sustained response.

Unspecific immunosuppressants are also associated with low response rates, although mainly older data are found in the literature. Because the extravascular hemolysis predominantly takes place in the liver, splenectomy is ineffective except in some rare cases of IgG-mediated disease or with a thermal amplitude approaching 37°C.

Therapy Directed at the Pathogenic B-Cell Clone

Although there are no randomized trials or formal approvals of any chemoimmunotherapy in CAD, remission after B cell–directed treatment has been confirmed in several systematic studies. Single-agent rituximab has shown a beneficial effect, is generally well tolerated, and has become the most commonly used therapy for CAD. Retreatment will often, but not always, succeed in relapsed disease. There are no published data on rituximab maintenance in CAD.

Bendamustine plus rituximab is preferred over rituximab monotherapy in the first line for severely affected patients who are able to tolerate chemoimmunotherapy. Otherwise, rituximab monotherapy is preferred.

Bortezomib monotherapy has also been studied in small trials, in which the overall response rate was approximately 31%. These response rates may seem low, but could be improved by using bortezomib in combinations or for an extended duration. Bortezomib-based regimens or, in highly selected cases, rituximab plus fludarabine, will be alternatives in the second or third line.

Complement Inhibitors in CAD

The first documentation of successful complement inhibition in IgM-mediated, complement-dependent AIHA was a case report describing therapy for CAD with the anti-C5 monoclonal antibody eculizumab. However, C5 inhibition does not block the C3b-mediated extravascular hemolysis. Therefore, not unexpectedly, efficient blockade of C5 resulted in only a small increase in Hb.

Classical pathway inhibition should be expected to work better. However, because patients with AIHA/CAD usually have sufficient endogenous C1 inhibitor production, C1 inhibitor therapy will require frequent and high doses and is probably not an attractive long-term approach. The humanized, C1-targeting monoclonal antibody sutimlimab is an emerging second-line option and may even be considered in the first line for initial treatment of severely anemic patients without disabling ischemic symptoms.

Complement modulation at the C3 level is also a promising approach. The C3 inhibitor pegcetacoplan showed high efficacy in phase II trials, inhibiting the classical and alternative complement pathways with favorable pharmacodynamic properties.

Future Therapeutic Prospects

The B-cell–targeting approach has proved highly beneficial and might be further developed, aiming at equally efficacious and less toxic treatment options. Novel B-cell–targeting agents, such as Bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase inhibitors, and B-cell lymphoma 2 inhibitors, are highly active in other clonal B-cell LPDs and have a strong mechanistic rationale in CAD.

For example, no trial has been published, but remission after therapy with the BTK inhibitor ibrutinib has been observed in single cases. Systematic studies on the safety and efficacy of these drugs in CAD are warranted. A phase II trial of the phosphatidylinositol 3-kinase inhibitor parsaclisib is ongoing in patients with AIHAs of any type.

As mentioned, emergence of long-lived plasma cells may play a major role in the long time to response for patients receiving B cell–directed chemoimmunotherapy and the modest but significant failure rate of these regimens. It is of interest, therefore, to explore the potential of efficient plasma cell–directed approaches as a supplement to these therapies in selected patients. Proteasome inhibitor–based combinations represent such a possibility.

Furthermore, daratumumab, a monoclonal antibody against CD38 and powerful plasma cell–targeting agent, showed favorable effects in a small number of patients with warm AIHA after stem cell transplantation. A recent case report described a rapid and convincing effect in a patient with CAD who had disabling agglutination-mediated ischemic symptoms and refractoriness to B cell–directed therapies. A small, systematic case series would be highly interesting.

Although the complement-directed therapies are still investigational, quite a lot of documentation has accumulated for sutimlimab. This drug will probably be available outside clinical trials in the near future. Additional clinical studies of pegcetacoplan are also warranted. Less documentation is available on other upstream complement inhibitors, such as the anti-C1q monoclonal antibody ANX005.

Complement inhibition in CAD will have some limitations. The ischemic symptoms are not complement-mediated and will not be relieved. Also, these therapies will have to be continued indefinitely to maintain their effect, as opposed to, for example, the four-cycle bendamustine-rituximab regimen, which is temporary and highly efficacious.

On the other hand, the upstream complement inhibitors are rapidly acting and probably relatively nontoxic. One would expect such therapies to be particularly helpful in severely anemic patients, those with acute exacerbations that do not resolve spontaneously, and those in whom chemoimmunotherapy has failed or is contraindicated. In some cases, complement inhibition may be used as a bridge to B cell–directed treatment.

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