Richter transformation (RT) of chronic lymphocytic leukemia (CLL) into high-grade lymphoma is a complication in 210% of patients. While development of diffuse large B-cell lymphoma (DLBCL) is most common, rare occurrences of Hodgkin lymphoma (HL) have been documented. Targeted therapy has durable antitumor activity in high-risk CLL, but 510% of patients treated with ibrutinib and 1125% of those treated with venetoclax on clinical trials developed RT. Views differ on whether RT occurs prior to, during, or even as a consequence of targeted therapy. Unfortunately, pretreatment tissue biopsies are often unavailable and the question remains debated. We described two patients with CLL diagnosed with HL after 6 months of Brutons tyrosine kinase inhibitor (BTKi) therapy. Review of histopathology in both pretreatment biopsies revealed that RT transformation was preexisting. Targeted therapy is increasingly used to treat CLL in both salvage and upfront settings. Disease progression on targeted therapy, especially within the first year, often manifests as RT, while progressive CLL tends to emerge after extended treatment. Historically, most patients with RT presented with DLBCL and rarely with HL. On targeted therapy, both DLBCL and HL have been described. Diagnosis of RT among a dense background of CLL can be challenging. Recognition of early transformation to HL is aided by the identification of characteristic ReedSternberg cells that express IHC markers distinct from CLL cells. Having diagnosed two patients with HL after 6 months on BTKi, we took advantage of this immunophenotype to reexamine pretreatment tissue biopsies for the presence of ReedSternberg cells. Although stains for CD15 and CD30 that helped to identify sites of HL were not part of our routine IHC studies, our experience suggests that they should be included in cases with a suspicion for RT. The delay in clinical diagnosis in our patients fits well with observations from several studies with a median of 4.57.5 months from initiation of targeted therapy to the diagnosis of RT. These data suggest that a low burden of transformed disease is already present before starting treatment. Two types of HL-RT have been described in the literature. Type 1 is characterized by ReedSternberg cells scattered in a background of CLL. In type 2HL-RT, ReedSternberg cells are present in a polymorphous, inflammatory background separate from CLL. Cases of HL-RT on BTKi, including the two patients reported here, have been of the type 1 variety and are suggested to represent histologic transformation of the underlying CLL. Known risk factors for RT include prior therapy and EBV reactivation. In a series of 69HL-RT cases, 76% of patients had been previously treated with 32% receiving fludarabine. Although one of our patients was previously treated with a fludarabine-based regimen, neither were positive for EBV. The diagnosis of RT requires a high index of suspicion in patients with CLL presenting for treatment. Since diffuse CLL involvement is common in pretreatment tissue biopsies, a thorough histopathological examination may identify a low burden of transformed disease at an early stage and allow for timely and appropriate management. Interestingly, targeted therapies such as ibrutinib and venetoclax have short-lived activity against DLBCL-RT and de novo DLBCL and HL. Therefore, it is possible that treatment with such agents could only delay the diagnosis of RT due to a transient improvement or delay in progression of disease. Our cases document that RT occurred before the initiation, and not as a result of, BTKi therapy. In a separate study, we have investigated host-related immunodeficiency in development of multiple myeloma (MM) from its precursor conditions (monoclonal gammopathy of undetermined significance, MGUS, smoldering multiple myeloma, SMM). In order to understand the underlying immune changes in this process, we characterized immune patterns from MGUS to SMM to MM. We further sought to identify potential novel immune biomarkers that may predict progression of SMM to MM. We characterized patterns of circulating lymphocytes in 181 patients using multiparametric flow cytometry. We found decrease in B-cells (p=.0003) and increase in T-cells (p=.037) sequentially from MGUS to SMM to MM. NK-cell proportions were unaltered. To gain insights into their functional variability, we further immunophenotypically characterized lymphocyte subsets, which uncovered differences in several subsets. Specifically, we found that SMM patients who eventually progressed to MM showed decreased proportions of CD57-CD56+(p=.0061) and CD57-CD16+(p=.035) lymphocyte subsets. We thus reported novel data characterizing the nature of host-related immunodeficiency in the development of MM. We showed gradual changes in lymphocyte subsets from MGUS to SMM to MM. These findings prompted suggestion that changes in CD57 lymphocyte subsets may serve as potential markers of progression from SMM to MM. Such markers could provide clinical guidance in managing myeloma precursor disease. In a separate study, we have investigated host-related immunodeficiency in development of multiple myeloma (MM) from its precursor conditions (monoclonal gammopathy of undetermined significance, MGUS, smoldering multiple myeloma, SMM). In order to understand the underlying immune changes in this process, we characterized immune patterns from MGUS to SMM to MM. We further sought to identify potential novel immune biomarkers that may predict progression of SMM to MM. We characterized patterns of circulating lymphocytes in 181 patients using multiparametric flow cytometry. We found decrease in B-cells (p=.0003) and increase in T-cells (p=.037) sequentially from MGUS to SMM to MM. NK-cell proportions were unaltered. To gain insights into their functional variability, we further immunophenotypically characterized lymphocyte subsets, which uncovered differences in several subsets. Specifically, we found that SMM patients who eventually progressed to MM showed decreased proportions of CD57-CD56+(p=.0061) and CD57-CD16+(p=.035) lymphocyte subsets. We thus reported novel data characterizing the nature of host-related immunodeficiency in the development of MM. We showed gradual changes in lymphocyte subsets from MGUS to SMM to MM. These findings prompted suggestion that changes in CD57 lymphocyte subsets may serve as potential markers of progression from SMM to MM. Such markers could provide clinical guidance in managing myeloma precursor disease.
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