Treatment with pembrolizumab can cause autoimmune hemolytic anemia and cold agglutinin disease (CAD), according to a case study published in BMJ Case Reports. The authors emphasize the importance of distinguishing between CAD caused by pembrolizumab and primary CAD.

“Think of CAD when [hemolytic anemia] is present along with cold agglutinins and steroid refractoriness,” the researchers wrote. They added that a bone marrow biopsy is needed to rule out B-cell lymphoproliferative disorder before attributing CAD to pembrolizumab.

The case presented a 65-year-old patient with non-small cell lung cancer being treated with pembrolizumab. The patient developed autoimmune hemolytic anemia during the treatment. This was first thought to be caused by pembrolizumab-induced hemolysis.

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Treatment was therefore halted and the patient was treated with steroids. However, this did not resolve hemolysis and blood agglutination in cold room temperatures. 

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Blood tests revealed high cold agglutinin titer and monoclonal IgM kappa protein, and the bone marrow biopsy showed marginal zone lymphoma. This confirmed low-grade B-cell lymphoma causing CAD. 

When the patient was treated with rituximab to deplete B-cells, hemolysis stopped. As a result, pembrolizumab was not the cause of the hemolysis, and treatment for lung cancer continued safely. 

“This case highlights the need to perform a full workup and not prematurely assume an uncommon autoimmune adverse event to be related to pembrolizumab when receiving the drug,” the researchers wrote. 

When CAD is diagnosed while a patient is on pembrolizumab or similar agents, a bone marrow biopsy test for whether the cold agglutinins are monoclonal or polyclonal can help identify whether or not CAD is induced by pembrolizumab. Cold agglutinins in primary CAD are monoclonal, while those in pembrolizumab-induced CAD are polyclonal. 

Differentiating between the 2 types of CAD is important, as treatment approaches are very different.


Karki NR, McElhone P, Savage N, Abdel Karim N. Diagnosis and management of cold agglutinin disease associated with low-grade B-cell lymphoma in a patient receiving pembrolizumab for lung cancer. BMJ Case Rep. 2021;16;14(8):e243751. doi:10.1136/bcr-2021-243751