Bortezomib Shows Promise for Treating Certain CAD Patients, Phase 2 Trial Finds

Cold agglutinin disease (CAD) patients who relapse after standard treatment could benefit from a short-term course of treatment with bortezomib, an approved therapy for certain cancers, a Phase 2 clinical trial shows.

Trial findings were published in the study, “Short course of Bortezomib in anemic patients with relapsed cold agglutinin disease, a phase II prospective gimema study,” in the journal Blood.

Cold agglutinin disease (CAD) is a chronic autoimmune condition where patients develop antibodies against their own red blood cells, causing their destruction (a process called hemolysis). These antibodies are cold-sensitive, meaning they are only reactive at a temperature below 30 degrees Celsius (86 degrees Fahrenheit), so effects could be minimized by avoiding cold exposure.

Nonetheless, hemoglobin level in these patients is around 89 grams per liter, whereas normal values should be above 120 grams per liter for females and 130 grams per liter for males.

CAD is a relatively rare disease that is estimated to only affect 15 percent of patients who have autoimmune hemolytic anemias (AIHAs). Treatment for these patients remains a challenge.

The standard therapy for CAD is rituximab (sold under the brand name Rituxan in the U.S., and MabThera in Europe, among others), but only 50 percent of patients respond to it, and the therapy’s effects last on average only 12 months. Rituximab’s efficacy is significantly enhanced when given with chemotherapy agents fludarabine or bendamustine, but these are also linked to adverse effects.

Bortezomib (brand name Velcade) is a proteasome inhibitor used to treat diseases linked to the abnormal production of antibodies, such as multiple myeloma, light-chain amyloidosis, and Waldenstrom’s macroglobulinemia.

Because B-cells (antibody-producing cells) are usually affected in CAD, the researchers in this study tested whether CAD patients could benefit from treatment with bortezomib.

They conducted an open-label Phase 2 trial (NCT01696474) that enrolled 21 patients, recruited from six centers, between April 2012 and March 2016. Patients were resistant to other therapies or relapsed after at least one previous treatment. Patients’ hemoglobin levels were less than 100 grams per liter during the two months prior to the beginning of the trial.

Patients were treated with a dose of 1.3 milligrams per square meter (mg/sqm), delivered by injection into the vein on days one, four, eight, and 11. They also received preventive treatment with 400 mg of the antiviral medication acyclovir (brand name Zovirax) twice a day, until one month after bortezomib treatment.

Results from 19 patients showed that the overall response was 31.6% — three patients achieved a complete response and another three a partial response. Four patients no longer required blood transfusions.

Four out of six patients maintained a good response after a median of 16 months of follow-up. At the last follow-up, all patients were alive with the exception of one patient who died due to septic shock (generalized infection) 10 months after entering the study.

Considering the whole treated group, median hemoglobulin levels rose from 87 to 96 grams per liter (g/L), but for responding patients, this increased even more, from a median of 85 to 114 g/L. Moreover, the levels of autoantibodies remained stable in 10 out of 13 patients.

Researchers found no correlation between patient characteristics and response to bortezomib.

They registered a total of 19 adverse events, which included headaches, diarrhea, increased bilirubin (a byproduct of the normal breakdown of red blood cells), anemia, and pulmonary embolism.

“This study shows that a short course of bortezomib may be effective in one third of patients with symptomatic CAD failing previous treatments, with acceptable toxicity, and long-lasting benefit in the majority of responding patients,” the researchers wrote.

Future studies should investigate the efficacy of a longer treatment period with bortezomib and assess its combination with other therapies such as rituximab to increase potential benefits for CAD patients.