Blood Advances in a Different Vein
Eculizumab Reduces Hemolysis and Transfusion Dependency
in Patients With Cold Agglutin Disease
Treatment with eculizumab, an in-
hibitor 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 hemo-
lytic anemia caused by immuno-
globulin M (IgM) autoantibodies
against red blood cell (RBC) anti-
gens,” Alexander Röth, MD, from
the department of hematology at
University Hospital Essen in Ger-
many, and co-authors explained.
“Most patients suffer from mild or
moderate anemia, with exacerba-
tion at cold temperature.”
While “drug treatment of
chronic CAD has so far been based
on cytoreduction, using approach-
es derived from the treatment of
lymphoma,” potential toxicity pre-
cludes their use in older patients.
The results from this trial sug-
gest 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 (Eculi-
zumab in cold agglutinin disease)
trial evaluated the safety and ef-
ficacy 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 reac-
tivity 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 symp-
toms or transfusion-dependence.
Impact of Eculizumab on Indicators of Hemolysis
in Patients With CAD
TABLE 2.
Laboratory Test
Normal Range
Lactate dehydrogenase, U/L
p Value
572 (534-685) 334 (243-567) 0.022
<22 46.2 (18.2-124.0) 30.0 (19.5-80.6) 0.844
Bilirubin, µmol/L 5.1-20.5 46.0 (34.2-68.4) 43.0 (20.0-61.6) 0.012
Haptoglobin, g/L 0.3-2.0 0.04 (0.03-0.05) 0.03 (0.02-0.05) 0.844
Hemopexin, g/L 0.5-1.2 0.47 (0.18-0.58) 0.85 (0.45-1.09) 0.013
Hemoglobin, g/dL 11.6-16.1 9.35 (8.80-10.80) 10.15 (9.00-11.35) 0.039
22-76 160.2 (99.1-185.5) 111.7 (67.4-142.6) 0.063
Reticulocytes, ×10 9 /L
Treatment with alkylating agents,
rituximab, human immunoglobu-
lins, or plasmapheresis was pro-
hibited 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 eculi-
zumab 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 post-
treatment observation phase. Two
patients discontinued: One left
the study due to clinical suspi-
cion 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 de-
creased 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 de-
hydrogenase level remained low
(268 U/L and 231 U/L).
–ALEXANDER RÖTH, MD
ASH Clinical News
Week 26
120-247
Free hemoglobin, mg/dL
“Our findings suggest that
eculizumab was able to control
hemolysis in patients with weak,
but not in patients with strong,
complement activation.”
60
Week 0
The post-treatment observation
phase showed increases in hemo-
globin and the plasma protein he-
mopexin 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: 160.2×10 9 /L
(range = 99.1-185.5) to
111.7×10 9 /L (range = 67.4-
142.5; p=0.063)
See full results in TABLE 2 . The he-
moglobin rise was paralleled by a
significant reduction in red blood
cell transfusion requirements,
the investigators reported, “with
three patients maintaining and
eight patients acquiring transfu-
sion independence (p=0.02).” The
median number of units trans-
fused was 0 (range = 0-12 units),
instead of an expected 2.6 units
(range = 0-20.9 units; p=0.06).
However, cold-induced circula-
tory symptoms, such as acrocya-
nosis or Raynaud syndrome, re-
mained 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 ampli-
tude (p=0.09 for the comparison
of 37°C vs. 4°-30°C). “Suppres-
sion 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 hemor-
rhage, 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 prob-
ably 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 am-
plitude is considered the most
relevant measure of disease sever-
ity: 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 con-
cluded. “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 relation-
ships with Roche and Alexion. ●
REFERENCE
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.
December 2018