Page 41 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
Figure 1. Management of cold agglutinin disease. DAT: direct antiglobulin test; CA: cold agglutinin; CAS: cold agglutinin syndrome; computed tomography; LDH: lactate dehydrogenase; EPO: erythropoietin; BR: bendamustine and rituximab; BTKi: Bruton tyrosine kinase inhibitor.
bine is efficacious (response rate: 62%; complete re- sponses: 38%) but associated with an increased risk of secondary malignancy and is therefore not a preferred op- tion.10,20 Based on a prospective study of 19 patients,21 the response rate to bortezomib-based treatment was 32%, although this was after only a single course of bortezomib. Bruton tyrosine kinase (BTK) inhibitors were effective in all four treated patients with relapsed CAD in a retrospec- tive report.22 There is a case report of the use of daratu- mumab in CAD.23
Clinical trials should be considered in relapsed disease. Promising studies have examined proximal complement inhibition to inhibit extravascular hemolysis. Complement inhibition necessitates indefinite treatment and fails to re- duce vascular symptoms. In a phase III study of anti-C1s, sutimlimab, versus best supportive care, it was seen that the complement inhibitor rapidly halted hemolysis, pro- duced transfusion independence in 73% of patients, in- creased hemoglobin concentration by more than 15 g/L and improved fatigue;24 this drug has now been approved by the Food and Drug Administration.24 The effect of com- plement inhibition on thrombosis has not been estab- lished; however, D-dimer and thrombin-antithrombin complex levels decreased on treatment.13,24 Use of the C5 inhibitor eculizumab rapidly abrogates the terminal com- plement pathway with a short time to response. However, in a phase II trial there was a marginal hemoglobin rise of 8 g/L.13 Proximal complement inhibition presumably has
greater effectiveness because it targets C3-mediated hemolysis via the liver, which is often predominant in CAD. Ongoing clinical trials of complement inhibition in CAD in- clude those studying the C3b inhibitor, pegcetacoplan (phase III, NCT05096403), the complement factor B in- hibitor, iptacopan (phase II, NCT05086744), the C1 esterase inhibitor, cinryze (phase II, 2012-003710-13/NL) and the C1s inhibitor BIVV020 (phase Ib, NCT04269551).
Acute life-threatening intravascular hemolysis may necessitate transfusion. Plasma exchange may be em- ployed provided that all priming fluids and the circuit ap- paratus are pre-warmed and that the replacement products are run through a warmer. Erythropoietin sup- port can be considered as erythropoietin can be inappro- priately low in autoimmune hemolytic anemia.25 Complement-directed therapy may act as a bridge for ri- tuximab combinations to target the underlying clone, which can take weeks to have an effect.
Cryoglobulinemia
Cryoglobulinemia is characterized by immunoglobulins that precipitate at temperatures below 37°C and redis- solve on warming. Monoclonal IgM can be associated with type I and type II cryoglobulinemia. Type I cryoglobuline- mia consists of monoclonal immunoglobulins only. In type II “mixed” cryoglobulinemia there is a monoclonal com-
Haematologica | 107 September 2022
2040