Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis—with comparison to Hodgkin-like lesion

Xiao, Wenbin; Chen, Wayne W.; Sorbara, Lynn; Davies-Hill, Theresa; Pittaluga, Stefania; Raffeld, Mark; Jaffe, Elaine S.

doi:10.1016/j.humpath.2016.04.019

Cited by 76 publications

(79 citation statements)

References 35 publications

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“…All of these agents are orally administered and in contrast to earlier generations of antineoplastic agents are typically prescribed until there is tumor progression, i.e., patients may be treated with these agents for months or years. None of these malignancies is typically associated with EBV, although high EBV copy number in blood has been reported in some patients with chronic lymphocytic leukemia (27,28), and chronic lymphocytic leukemia may evolve into EBV-associated diffuse large B cell lymphoma or Hodgkin lymphoma (29,30). We suspect that the BTK and PI3K␦ inhibitors will impact the long-term EBV reservoir and EBV viremia.…”

Section: Discussionmentioning

confidence: 97%

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Kosowicz

Lee

Peiffer

et al. 2017

J Virol

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Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib.IMPORTANCE EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors.KEYWORDS B cell receptor pathway, cyclosporine, dasatinib, Epstein-Barr virus, ibrutinib, idelalisib, lytic infection, rapamycin, tacrolimus, mTOR E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus infection that is maintained in a pool of resting memory B cells following primary infection (1-3).The disappearance of B cells from blood as assessed by flow cytometry following treatment with a B cell-targeting monoclonal antibody commonly results in an inability to detect EBV DNA in peripheral blood mononuclear cells (PBMCs) (4). The reservoir in B cells appears to be necessary to maintain the virus as evidenced by the observation that chronic infection is not established in patients with Bruton agammaglobulinemia who lack B cells (3). B cells not only harbor the virus, but the character of the B cells that harbor virus influence viral gene regulation. In vitro, EBV infection of B cells results in immortalized lymphoblastoid cell lines expressing eight or more latency antigens, whereas in vivo, in healthy seropositive adults, the B cells that harbor viral genomes demonstrate very restricted viral gene expression. The germinal center reaction that occurs in lymphoid tissue is hypothesized to play a key role in downmodulating viral gene expression (1). In some B cell tumor lines, B cell receptor (BCR) signaling is a potent activator of EBV lytic gene expression (5). EBV gene expression and particularly

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Section: Discussionmentioning

confidence: 97%

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Kosowicz

Lee

Peiffer

et al. 2017

J Virol

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“…Patients with HL RT may represent a prognostically favorable subgroup, as has been previously reported. 18,21 Although historically DLBCL RT is often associated with dismal outcomes, 22 some patients with RT emerging on venetoclax can achieve durable responses to salvage therapy. Patients in our cohort whose RT was controlled successfully by salvage therapy demonstrated a response in residual CLL with BTK inhibition, leading to prolonged survival.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax

Anderson

Tam

Lew

et al. 2017

Blood

162

143

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Key Points• Complex karyotype and fludarabine refractoriness are key risk factors for progression of CLL on venetoclax.• Bruton tyrosine kinase inhibitors are active in patients with CLL after prior therapy with venetoclax.The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P 5 .003). Among patients who received the recommended phase 2 dose of venetoclax or higher ( ‡400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P 5 .002 and 6.6 [1.5-29.8]; P 5 .005, respectively), whereas del(17p) and/or TP53 mutation were not (P 5 .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy. (Blood. 2017;129(25):3362-3370)

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“…ZAP-70 staining has been used by some researchers to elucidate RS cells arising from mutations in SLL cells. This marker was negative in cases where RS cells were clonally related to SLL cells and positive in others which were unrelated and emerged spontaneously 7. Other mechanisms thought to play an instrumental role include immunosuppression, an important component of SLL, which sets the stage for the development of other malignancies, including HL 8 9.…”

Section: Discussionmentioning

confidence: 99%

Small lymphocytic lymphoma with Reed Sternberg cells: a diagnostic dilemma

2017

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Reed Sternberg (RS) cells in the setting of small lymphocytic lymphoma (SLL) can complicate the histopathological diagnosis. We report a case of a man aged 54 years who presented with cervical lymphadenopathy. Resection of the lymph node was performed and sent for histopathological evaluation to a local laboratory. A diagnosis of SLL with Classic Hodgkin's lymphoma (CHL) was made. The medical oncologist who encountered this diagnosis for the first time sent the biopsy blocks to our laboratory for a second opinion. On review of the biopsy and immunohistochemical stains, it showed typical SLL morphology and immunophenotype. Focally, it showed large mononuclear RS type cells; however, no typical background of CHL was seen. The diagnosis was revised to 'SLL with RS like cells with no convincing evidence of CHL'. The patient was subsequently treated as a case of SLL and no progression was observed on a follow-up of 5 years.

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Hodgkin lymphoma variant of Richter transformation: morphology, Epstein-Barr virus status, clonality, and survival analysis—with comparison to Hodgkin-like lesion

Cited by 76 publications

References 35 publications

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax

Small lymphocytic lymphoma with Reed Sternberg cells: a diagnostic dilemma

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