The antibody-based medication, normally used to treat myeloma, may offer an alternative to CAD patients who fail to respond to other therapies, the researchers said.
The study, “The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease,” was published in the journal Autoimmune and Autoinflammatory Disorders.
Because CAD is associated with the abnormal expansion of B-cells, a type of antibody-producing immune cells, many medications now used to treat it were originally developed for blood cancers, such as myeloma and leukemia, and other disorders associated with excessive immune cell proliferation. Rituximab, marketed as Rituxan in the U. S. and as MabThera in Europe, is one of these medications.
Daratumumab, marketed as Darzalex, was found to be beneficial in certain patients with hard-to-treat CAD who failed to respond to rituximab. Yet, such reports are sparse and the therapy’s effect on immune response mediators remains largely unknown.
The medication consists of an antibody that blocks the activity of CD38, a protein mainly found on the surface of mature immune B-cells, called plasma cells.
Here, physicians at the University of Milan, in Italy, used daratumumab to treat a man with CAD who had relapsed after receiving several other therapies.
The patient was first treated at an Italian hospital in June 2011 with severe cold-related circulatory symptoms. After excluding genetic factors, doctors found evidence of low-titer cold agglutinins and a positive direct antiglobulin test — called the Coombs test — which detects antibodies directed against red blood cells. Of note, cold agglutinins are the self-reactive antibodies that bind and destroy red blood cells at low temperatures in people with CAD.
A bone marrow examination revealed the patient had an abnormally high number of cells, along with defects in red blood cell maturation, an increased number of immature red blood cells, and plasma cell infiltration. All of these findings were consistent with a CAD diagnosis.
The patient required intense blood transfusions of two red blood cell units every 15–20 days on average, despite receiving erythropoietin (EPO), a treatment that promotes red blood cell production and increases the amount of the oxygen-carrying hemoglobin protein normally found in these cells. EPO has been used to safely and effectively treat CAD in the past, although it proved ineffective in this case.
Despite achieving a complete response — meaning he no longer showed any signs of disease — that lasted for more than two years, the patient’s hemoglobin levels dropped low enough to cause disabling circulatory symptoms in 2018.
Discovering the same bone marrow findings as before, the doctors treated him with another course of bortezomib and EPO, which failed. The patient was then started on rituximab, which also failed to elicit a therapeutic response.
A subsequent bone marrow examination revealed defects in red blood cell maturation with increased plasma cell infiltration and fibrosis, or tissue scarring. There was no sign, however, of any underlying genetic cause.
With the patient remaining severely anemic and dependent on regular blood transfusions, doctors started him on daratumumab in June 2019.
His anemia gradually eased, to the point at which he no longer needed transfusions and his circulatory symptoms disappeared. Moreover, the patient tolerated daratumumab well and experienced no undesirable side effects.
Biochemical analyses found evidence that daratumumab acted by altering the levels of various cell signaling molecules, known as cytokines, which are released by cells of the immune system.
After six cycles of treatment, the patient’s bone marrow evaluations showed normal cell growth and decreased plasma cell infiltration. Yet, his low titer of cold agglutinins remained unchanged. At this point, the patient was stable and continued to receive daratumumab up until the time this report was written.
A literature review of other cases in which daratumumab was used revealed a number of successes among patients with CAD or similar conditions who had received several treatments. These patients tended to respond well to daratumumab in a short period of time and over a variable number of cycles.
“Our case, along with previous reports, indicates that daratumumab is effective in CAD in ameliorating anemia and improving disabling circulatory symptoms, providing an additional therapeutic option for the refractory disease,” the investigators concluded.
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