Cold agglutinin disease (CAD) is defined as a chronic autoimmune hemolytic anemia (AIHA) with
a monospecific direct antiglobulin test (DAT) strongly positive for C3d and the presence of
cold agglutinins (CA; titer ≥ 64 at 4°C). Patients may have a B-cell clonal
lymphoproliferative disorder (LPD) detectable in blood or marrow but no clinical or
radiological evidence of malignancy. CAD can lead to AIHA, peripheral ischemic symptoms
(cold-induced peripheral symptoms such as acrocyanosis etc.), or both. The CAs are typically
monoclonal IgM antibodies produced by the clonal B-cells, usually IgM kappa with specificity
for the I antigen on erythrocytes. There is no curative treatment. Current treatment options
include rituximab monotherapy, however this has only a limited and short-lasting effect.
Rituximab in combination with chemotherapy induces deeper and more durable responses, however
since CAD patients typically do not have an overt malignancy this comes with concerns about
short- and long-term toxicity. Novel complement inhibitors may be effective for the hemolysis
but are not expected to be effective against cold induced peripheral symptoms while this is
directly IgM mediated. Bruton Tyrosine Kinase inhibitors (BTKis) are effective in many B-cell
lymphoproliferative disorders including the IgM producing clone of Waldenström
macroglobulinemia (WM) and were very effective on both AIHA and peripheral ischemic symptoms
in patients with CAD based on retrospective data.
Phase:
Phase 2
Details
Lead Sponsor:
Stichting Hemato-Oncologie voor Volwassenen Nederland