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Home » Finally, there is growing evidence that AIC may evolve to overt clonal diseases of myeloid or lymphoid lineages and no predictors are available (138C141)

Finally, there is growing evidence that AIC may evolve to overt clonal diseases of myeloid or lymphoid lineages and no predictors are available (138C141)

Finally, there is growing evidence that AIC may evolve to overt clonal diseases of myeloid or lymphoid lineages and no predictors are available (138C141). Genomic studies are limited in these forms, except for recurrent mutations of KMT2D and CARD11 in chilly agglutinin disease, which is considered a clonal B-cell lymphoproliferative disorder resulting in AIHA. In this manuscript, we review the most recent literature on AIHA and ITP secondary to CLL, focusing on available molecular evidences of pathogenic, clinical, and prognostic relevance. = 13) (26) and most CLL-AIC cases were able to discontinue AIC-therapy after a median of 4.7 months (= 301 of whom 7% with ongoing AIC therapy) (27). Comparable data were reported Scutellarin in a more recent study of 193 patients: 67% of 29 cases with AIC pre-ibrutinib could discontinue/taper AIC treatment and new-onset AIC Scutellarin occurred in 6% (all with unmutated IGHV) (28). Recent evidences suggest an inhibitory role of ibrutinib on autoreactive T Scutellarin cells, through interleukin-2-inducible kinase (ITK)suppression, leading the way for its use in T-cell mediated autoimmune conditions (i.e., graft vs. host disease) (29). Regarding other small molecules, limited data are available for idelalisib (that targets phosphoinositide 3-kinase), and venetoclax (a BCL-2 antagonist), although the presence of autoimmune phenomena was an exclusion criteria in various trials. Concerning venetoclax, it has been reported to be associated to the occurrence, although rarely, of AIHA in large CLL registrative trials (30). Interestingly, increased incidence of autoimmune complications (hepatitis, colitis, and pneumonitis) has been reported for idelalisib (31, 32). Management of Autoimmune Hemolytic Anemia Secondary to CLL Diagnosis Management of AIHA in CLL requires the evaluation and exclusion of the other possible causes of anemia, including bone marrow infiltration/failure, bleeding, vitamin or iron deficiencies, and renal disease. As previously suggested, a diagnosis of AIHA can be established in the presence of Hb 11 g/dL, no chemotherapy in the previous month, variable alteration of hemolytic markers (increased unconjugated bilirubin, elevated lactate dehydrogenase, consumption of haptoglobin, increased absolute reticulocyte counts), and the positivity of the direct antiglobulin test (DAT) (1, 33). The latter allow to distinguish warm (wAIHA: DAT positive for IgG or IgG+C3d at low titer and unfavorable autoagglutination at 20C) from chilly (cAIHA) cases (DAT positive for C3d and positive autoagglutination at 20C). Of notice, CLL itself may be a confounder in the differential diagnosis, since LDH may be elevated during disease progression, haptoglobin increased due to chronic/acute inflammation, and reticulocytosis may be absent or inadequate due to bone marrow infiltration or suppression by cytokine storm and/or anti-erythroblasts antibodies (1). The latter, demonstrated in a proportion of CLL cases through the mitogen-stimulated TSPAN3 DAT, were associated to increased IL-4 and IFN- production, and may contribute to ineffective erythropoiesis (34). Furthermore, DAT positivity does not necessarily mean AIHA and in a longitudinal study of DAT+CLL cases only one third developed clinically overt hemolysis (35). Conversely, DAT unfavorable AIHA cases may also be present (36), possibly due to the low-affinity or to the very small number of autoantibodies. In this context, the use of more sensitive techniques (microcolumn and solid-phase assessments, or mitogen-stimulated DAT) may be useful (34). Finally, Bone marrow biopsy is usually necessary to document CLL infiltration and to rule out other causes (including bone marrow failure). Treatment As regards therapy (Table 1), the acuteness of onset, the severity of the anemia and the degree.

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