The number of cases of cold agglutinin disease (CAD) and other hematological diseases associated with the use of immunotherapeutic agents is escalating, according to a new study published in Hematology/Oncology Clinics of North America.

Hwang et al reported that the rise of immune-related CAD and other hematologic adverse events might relate to the increasing use of immune checkpoint inhibitors (ICIs) in the management of neoplastic pathologies. However, the precise frequency of immune-related adverse events to ICIs is not yet known, the authors said.

A different study reported that immune-related adverse events accounted for 0.06% to 0.25% of all adverse reactions to ICIs, mostly after using programmed earth 1 protein or programmed cell death ligand 1 targeting agents. Among these, CAD was less frequently diagnosed than immunoglobulin G-positive warm autoimmune hemolytic anemia (AIHA). Melanoma and nonsmall cell lung cancer are the malignancies mostly associated with such hematologic diseases in 41% and 26% of the cases, respectively, followed by renal cell carcinoma, Hodgkin lymphoma, and other skin cancers.

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Patients with suspected hematologic immune-related adverse events, acrocyanosis secondary to cold temperatures, Raynaud phenomenon, and livedo reticularis have signs and symptoms that suggest CAD. A peripheral blood smear reporting red cell agglutination is of utmost importance to confirm the diagnosis.

“Diagnostic criteria for [immune-related CAD] are even more difficult to delineate than those for warm [immune-related AIHA], primarily due to the paucity of reported cases,” the authors said. “Given this, the authors recommend using similar diagnostic criteria to those for non-ICI-associated CAD, with the important additional history of exposure to an ICI as a required criterion.”

Although sometimes challenging, the differential diagnosis between CAD and AIHA is critical since the treatment for each entity widely differs. For CAD, drugs that target B-cell lymphoproliferation, such as rituximab, are the first line, given the promising results in previous trials. Conversely, steroids and splenectomy have shown limited effects on remission.

However, specific treatment for immune-related CAD is not well defined, mostly due to the relative lack of published cases. Current recommendations include the same treatment scheme mentioned above with the caveat to avoid alkylating agents.


Hwang S, Saliba A, Wolanskyj-Spinner A. Immunotherapy-associated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. Published online April 1, 2022. doi:10.1016/j.hoc.2021.11.002