Blood Cancer Therapy May Be Effective for Difficult-to-treat CAD, Case Study Suggests

Blood Cancer Therapy May Be Effective for Difficult-to-treat CAD, Case Study Suggests
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Daratumumab, a therapy used to treat myeloma patients, effectively eased painful and disabling symptoms in a man with cold agglutinin disease (CAD) who failed to respond to rituximab, a case report showed.

If this therapeutic response is confirmed in other patients, daratumumab — sold by Janssen Pharmaceuticals under the brand name Darzalex — may represent a new approach for treating people with CAD.

The case study, “Daratumumab for disabling cold agglutinin disease refractory to B-cell directed therapy,” was published in the American Journal of Hematology.

Daratumumab, initially created by Genmab, is an antibody that blocks the activity of CD38, a protein mainly found on the surface of plasma cells — the matured form of immune B-cells.

The therapy is approved for the treatment of myeloma, a type of blood cancer in which mutations in plasma cells lead to their uncontrolled growth in the bone marrow, affecting the production of other blood and immune cells.

B-cells normally produce antibodies against harmful invaders such as viruses, bacteria, and fungi. However, in autoimmune diseases, such as CAD, some B-cells wrongly produce autoantibodies against the body’s own cells or tissues.

Autoantibodies in CAD, called cold agglutinins, bind to red blood cells when exposed to cold temperatures and activate their destruction. Such autoantibodies are mostly immunoglobulins M (IgM). The disorder is thought to be associated with an abnormal growth of B-cells, called B-cell lymphoproliferative disease.

As such, currently used CAD treatments include the B-cell targeted therapy rituximab — marketed as Rituxan in the U. S., by Genentech and Biogen, and as MabThera in Europe, by Roche. Rituximab is also approved for the treatment of some B-cell cancers other than myeloma.

Now, researchers at the University College London Hospitals NHS Foundation Trust, in London, and a colleague in Norway, reported the case of a Caucasian man successfully treated for CAD with daratumumab after the failure of rituximab.

The patient was diagnosed at age 48 with CAD, with the presence of IgM cold agglutinins. His main symptom was painful and disabling acrocyanosis — characterized as skin discoloration due to poor blood circulation, especially in the fingers and toes — worsened by exposure to cold temperatures. The disorder led to his early retirement as an aeronautical engineer.

At the time of his diagnosis, in 2011, the red blood cell destruction was being naturally well compensated, according to the researchers. There were no signs of monoclonal cold agglutinins — produced by plasma cells that originated from a single, abnormal plasma cell that divides in an uncontrolled manner — or major problems in the bone marrow.

Notably, the researchers said that only 10% of CAD patients have life-changing symptoms associated both with low oxygen and well-compensated red blood cell production.

Several initial treatments failed to produce meaningful clinical responses. Rituximab, given both alone and in combination with the steroid prednisolone, did not significantly ease the man’s symptoms. Plasmapheresis — a process in which the plasma from a patient’s blood is replaced with fresh plasma or a plasma substitute — also was not successful, due to red blood cell clumping within the equipment “despite active warming,” the researchers wrote.

Treatment with the proteasome inhibitor bortezomib, sold as Velcade and used to treat multiple myeloma and a type of lymphoma, also failed. Moreover, it resulted in symptom worsening, with intense acrocyanosis. That therapy was thereby discontinued for this patient.

About four years later, a bone marrow biopsy revealed higher numbers of cells positive for CD138, another marker of plasma cells. Again, however, no monoclonal cold agglutinins were detected.

Blood circulation-related symptoms persisted and the man experienced anemia, with low levels of hemoglobin, which are the molecules in red blood cells that transport oxygen throughout the body.

He received other treatment combinations, including the immunotherapy lenalidomide (sold as Revlimid),the cancer medicine cyclophosphamide, and steroids. But the patient remained markedly impaired, unable to work, and significantly restricted in his daily activities.

Genetic testing showed a mutation in the patient’s MYD88 gene. That mutation, called L265P, is usually associated with B-cell malignancies, but not with CAD-associated B-cell lymphoproliferative disease.

As described in the case study, the doctors now tried treatment with daratumumab. The medication initially was given in a dose of 16 mg/kg once a week for weeks 1 to 8. For weeks 9 to 24, daratumumab was given every two weeks, and then every four weeks thereafter.

Within the first two weeks of treatment, the patient reported a significant reduction in acrocyanosis and the ability to enjoy previously prohibited activities. He also had a significant increase in hemoglobin levels and normalization of markers of red blood cell destruction. Bone marrow analysis indicated residual abnormalities.

“This is the first report of successful treatment with daratumumab in CAD,” the researchers wrote.

“The rapid and marked clinical and biochemical response was striking and highly meaningful to the patient, who is now seeking to return to work,” they added.

Using recent international guidelines, the scientists classified the patient’s CAD as primary. They hypothesized that B-cell depleting therapies may have allowed the growth and maturation of B-cells resistant to such treatment, but vulnerable to plasma cell-directed therapies such as daratumumab.

“Further work is required to fully establish the mechanism of action,” the team wrote.

But if their hypothesis is confirmed, the researchers said daratumumab may be a new and attractive approach for CAD patients with disabling symptoms who do not respond to B-cell targeted therapies.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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  • CAD, daratumumab
  • Rituximab

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