Cold agglutinin–associated B-cell lymphoproliferative disease shows highly recurrent gains of chromosome 3 and 12 or 18

Małecka, Agnieszka; Delabie, Jan; Østlie, Ingunn; Tierens, Anne; Randen, Ulla; Berentsen, Sigbjørn; Tjønnfjord, Geir E.; Trøen, Gunhild

doi:10.1182/bloodadvances.2020001608

Cited by 32 publications

(19 citation statements)

References 26 publications

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“…Next-generation sequencing of bone marrow B-cells revealed recurrent KMT2D and CARD11 gene mutations in CAD patients [61]. The findings of a current study using cytogenetic microarrays and exome sequencing allowed for the identification of highly recurrent increases of chromosomes 3 and 12 or 18 in CAD-associated lymphoproliferative disease [62]. Furthermore, these genetic features of chromosome instability were similar to those demonstrated in nodal and extranodal marginal zone lymphoma (MZL) [63].…”

Section: Pathogenesis Of Aihasupporting

confidence: 60%

Autoimmune hemolytic anemia: current knowledge and perspectives

et al. 2020

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Autoimmune hemolytic anemia (AIHA) is an acquired, heterogeneous group of diseases which includes warm AIHA, cold agglutinin disease (CAD), mixed AIHA, paroxysmal cold hemoglobinuria and atypical AIHA. Currently CAD is defined as a chronic, clonal lymphoproliferative disorder, while the presence of cold agglutinins underlying other diseases is known as cold agglutinin syndrome. AIHA is mediated by autoantibodies directed against red blood cells (RBCs) causing premature erythrocyte destruction. The pathogenesis of AIHA is complex and still not fully understood. Recent studies indicate the involvement of T and B cell dysregulation, reduced CD4+ and CD25+ Tregs, increased clonal expansions of CD8 + T cells, imbalance of Th17/Tregs and Tfh/Tfr, and impaired lymphocyte apoptosis. Changes in some RBC membrane structures, under the influence of mechanical stimuli or oxidative stress, may promote autohemolysis. The clinical presentation and treatment of AIHA are influenced by many factors, including the type of AIHA, degree of hemolysis, underlying diseases, presence of concomitant comorbidities, bone marrow compensatory abilities and the presence of fibrosis and dyserthropoiesis. The main treatment for AIHA is based on the inhibition of autoantibody production by mono- or combination therapy using GKS and/or rituximab and, rarely, immunosuppressive drugs or immunomodulators. Reduction of erythrocyte destruction via splenectomy is currently the third line of treatment for warm AIHA. Supportive treatment including vitamin supplementation, recombinant erythropoietin, thrombosis prophylaxis and the prevention and treatment of infections is essential. New groups of drugs that inhibit immune responses at various levels are being developed intensively, including inhibition of antibody-mediated RBCs phagocytosis, inhibition of B cell and plasma cell frequency and activity, inhibition of IgG recycling, immunomodulation of T lymphocytes function, and complement cascade inhibition. Recent studies have brought about changes in classification and progress in understanding the pathogenesis and treatment of AIHA, although there are still many issues to be resolved, particularly concerning the impact of age-associated changes to immunity.

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Section: Pathogenesis Of Aihasupporting

confidence: 60%

Autoimmune hemolytic anemia: current knowledge and perspectives

et al. 2020

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“…A recent study found trisomy 3 (+3 or +3q) in all of 12 samples from CAD patients who participated in a clinical trial. Nine of these had an additional trisomy 12 or 18, but never both (19). Malecka et al also found that the Ig light chain gene IGKV3-20 and, to lesser extent, the similar IGHV3-15 gene are used in most patients (74%) and might contribute to the I antigen binding.…”

Section: Origin Of Cold Agglutininsmentioning

confidence: 94%

“…There may be occasional cases with CA titer < 64 (3,16)." By definition, "patients may have a B-cell clonal lymphoproliferative disorder (LPD) detectable in blood or marrow but no clinical or radiological evidence of malignancy" (3), and there is evidence that CAD is a clonal LPD of the bone marrow in most, probably all cases (5,(17)(18)(19). This distinct clinicopathological entity should be called a disease, not syndrome (3,20).…”

Section: Introductionmentioning

confidence: 99%

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

2020

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Autoimmune hemolytic anemias mediated by cold agglutinins can be divided into cold agglutinin disease (CAD), which is a well-defined clinicopathologic entity and a clonal lymphoproliferative disorder, and secondary cold agglutinin syndrome (CAS), in which a similar picture of cold-hemolytic anemia occurs secondary to another distinct clinical disease. Thus, the pathogenesis in CAD is quite different from that of polyclonal autoimmune diseases such as warm-antibody AIHA. In both CAD and CAS, hemolysis is mediated by the classical complement pathway and therefore can result in generation of anaphylotoxins, such as complement split product 3a (C3a) and, to some extent, C5a. On the other hand, infection and inflammation can act as triggers and drivers of hemolysis, exemplified by exacerbation of CAD in situations with acute phase reaction and the role of specific infections (particularly Mycoplasma pneumoniae and Epstein-Barr virus) as causes of CAS. In this review, the putative mechanisms behind these phenomena will be explained along with other recent achievements in the understanding of pathogenesis in these disorders. Therapeutic approaches have been directed against the clonal lymphoproliferation in CAD or the underlying disease in CAS. Currently, novel targeted treatments, in particular complement-directed therapies, are also being rapidly developed and will be reviewed.

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“…Unlike warm autoimmune hemolytic anemia, cold agglutinin disease (CAD) is a clonal hematologic disorder. Primary CAD is a distinct low grade lymphoproliferave disorder [ 31 , 32 , 33 ], with discernible histologic [ 31 ] and flow cytometric characteristics [ 32 ], immunoglobulin heavy and light chain gene features [ 33 ], cytogenetic abnormalities [ 34 ], and recurrent somatic mutations on next generation sequencing [ 35 ]. The pathogenic IgM is monoclonal, with kappa light chain specificity in 85% of cases [ 22 , 36 , 37 ].…”

Section: Aiha Pathophysiologymentioning

confidence: 99%

Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia

Murakhovskaya

2020

JCM

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Autoimmune hemolytic anemia is a rare condition characterized by destruction of red blood cells with and without involvement of complement. It is associated with significant morbidity and mortality. In warm autoimmune hemolytic anemia, less than 50% of patients remain in long-term remission following initial steroid therapy and subsequent therapies are required. Cold agglutinin disease is a clonal hematologic disorder that requires therapy in the majority of patients and responds poorly to steroids and alkylators. Rituximab has a favorable toxicity profile and has demonstrated efficacy in autoimmune hemolytic anemia in first-line as well as relapsed settings. Rituximab is the preferred therapy for steroid refractory warm autoimmune hemolytic anemia (wAIHA) and as part of the first- and second-line treatment of cold agglutinin disease. This article reviews the mechanism of action of rituximab and the current literature on its role in the management of primary and secondary warm autoimmune hemolytic anemia and cold agglutinin disease.

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Cold agglutinin–associated B-cell lymphoproliferative disease shows highly recurrent gains of chromosome 3 and 12 or 18

Cited by 32 publications

References 26 publications

Autoimmune hemolytic anemia: current knowledge and perspectives

Autoimmune hemolytic anemia: current knowledge and perspectives

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia

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