For example, TP53 disruption and unmutated status of IGHV genes are well-established predictors of chemorefractoriness that mandate treatment with targeted agents (BCR and/or BCL2 inhibitors) that can circumvent, at least in part, the CLL refractoriness to chemo-immunotherapy (CIT). This evidence concerns the gene BCL2 and B-cell chronic lymphocytic leukemia.