Treatment with eculizumab, an inhibitor of the terminal complement pathway, reduced hemolysis and transfusion-dependence in patients with cold agglutin disease (CAD). However, it had no effect on cold-induced circulatory symptoms, according to results from a phase II trial published in Blood Advances.
“CAD is a rare form of hemolytic anemia caused by immunoglobulin M (IgM) autoantibodies against red blood cell (RBC) antigens,” Alexander Röth, MD, from the department of hematology at University Hospital Essen in Germany, and co-authors explained. “Most patients suffer from mild or moderate anemia, with exacerbation at cold temperature.”
While “drug treatment of chronic CAD has so far been based on cytoreduction, using approaches derived from the treatment of lymphoma,” potential toxicity precludes their use in older patients.
The results from this trial suggest that “complement inhibition [via eculizumab] is a well-tolerated alternative in patients ineligible for or not responding to B-cell–directed therapies, when hemolysis is the leading cause of morbidity.”
The open-label, prospective, nonrandomized DECADE (Eculizumab in cold agglutinin disease) trial evaluated the safety and efficacy of eculizumab in 13 patients: 12 with chronic CAD and one with acute cold agglutinin syndrome. CAD was defined by hemolysis with a cold agglutinin titer ≥64 at 4°C and a monospecific direct antiglobulin test with strong reactivity against the complement C3d (a breakdown product of C3b) and negative or weak reactivity against immunoglobulin G.
Participants were ≥18 years old (median age = 74 years; range = 64-80 years) and required treatment because of anemia-related symptoms or transfusion-dependence. Treatment with alkylating agents, rituximab, human immunoglobulins, or plasmapheresis was prohibited at least four weeks before screening.
Nine patients were transfusion-dependent, with a median of 6 units transfused in the preceding 12 months (range = 2-32 units).
Patients received eculizumab 600 mg weekly for four weeks, followed one week later by eculizumab 900 mg every other week through 26 weeks of treatment.
Eleven patients completed the 26-week treatment phase, at which point they were given the option to continue eculizumab, then monitored through a posttreatment observation phase. Two patients discontinued: One left the study due to clinical suspicion of peritonitis and one left because the underlying Raynaud syndrome did not respond to eculizumab.
From baseline to the last day of therapy, patients’ median lactate dehydrogenase levels decreased from 572 U/L to 334 U/L (p=0.0215), the study’s primary endpoint. Seven of 13 patients showed a lactate dehydrogenase decrease ≥250 U/L.
In the two patients who elected to continue eculizumab beyond week 26, the lactate dehydrogenase level remained low (268 U/L and 231 U/L).
The posttreatment observation phase showed increases in hemoglobin and the plasma protein hemopexin and decreases in bilirubin and reticulocytes – signs of reduced hemolysis:
- Hemoglobin: 9.35 g/dL (range = 8.80-10.80) to 10.15 g/dL (range = 9.00-11.35; p=0.040)
- Hemopexin: 0.47 g/L (range = 0.18-0.58) to 0.85 g/L (range = 0.45-1.09; p=0.013)
- Bilirubin: 46.0 mmol/L (range = 34.2-68.4) to 43.0 mmol/L (range = 20.0-61.6; p=0.012)
- Reticulocytes: 160.2×109/L (range = 99.1-185.5) to 111.7×109/L (range = 67.4-142.5; p=0.063)
See full results in TABLE. The hemoglobin rise was paralleled by a significant reduction in red blood cell transfusion requirements, the investigators reported, “with three patients maintaining and eight patients acquiring transfusion independence (p=0.0215).” The median number of units transfused was 0 (range = 0-12 units), instead of an expected 2.6 units (range = 0-20.9 units; p=0.063).
However, cold-induced circulatory symptoms, such as acrocyanosis or Raynaud syndrome, remained unaffected by eculizumab.
Patients with cold agglutinins with a thermal amplitude of 37°C tended to have less pronounced lactate dehydrogenase responses than patients with cold agglutinins with a narrower thermal amplitude (p=0.090 for the comparison of 37°C vs. 4°-30°C). “Suppression of hemolysis caused by cold agglutinins with a wide thermal amplitude may require higher eculizumab doses than used here,” the authors concluded.
Thirteen patients experienced a total of 37 adverse events (AEs), including hemorrhoidal hemorrhage, fatigue, muscle cramps, arterial sclerosis, hypertension, pruritis, and limb pain. Thirteen AEs (occurring in 4 patients) were classified as possibly related to treatment, while one case of severe pneumonia was considered probably related to treatment. Notably, there were no meningococcal infections observed in this trial, despite the recognized increased risk of this toxicity in patients receiving eculizumab.
“In CAD, the thermal amplitude is considered the most relevant measure of disease severity: the higher the temperature at which the antibody can react with the cell, the greater the ability to fix complement and the greater the ensuing damage,” the authors concluded. “Our findings suggest that eculizumab was able to control hemolysis in patients with weak, but not in patients with strong, complement activation.”
The study is limited by the open-label and non-randomized design, as well as the small patient population. Follow-up was also limited in assessing response duration.
Alexion, supported the trial. The authors report financial relationships with Roche and Alexion.
Röth A, Bommer M, Huttmann A, et al. Eculizumab in cold agglutinin disease (DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Advances. 2018;2:2543-9.