Biology and Treatment of Richter Transformation

Condoluci, Adalgisa; Rossi, Davide

doi:10.3389/fonc.2022.829983

Cited by 37 publications

(27 citation statements)

References 118 publications

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“…Therefore, there are no conclusive data regarding the risk of Richter’s transformation under BTK therapies. In our patient, Richter’s transformation was observed only after three months under ibrutinib, earlier than that of other reported cases and that of non-ibrutinib treated subjects (3 vs. 15.5 vs. 10 months, respectively); however, overall survival was similar to that of non-ibrutinib treated patients (23 vs. 21 months, respectively), as already reported in the literature [ 33 ].…”

Section: Discussionsupporting

confidence: 81%

Hodgkin Lymphoma and Hairy Cell Leukemia Arising from Chronic Lymphocytic Leukemia: Case Reports and Literature Review

D’Addona

Giudice

Pezzullo

et al. 2022

JCM

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Richter’s syndrome represents the progression of chronic lymphocytic leukemia (CLL) to more aggressive diseases, most frequently diffuse large B-cell lymphoma, while Hodgkin’s lymphoma (HL) and hairy cell leukemia (HCL) are rarely described. The first case involved a 67-year-old man with a diagnosis of a high-risk stage-II CLL treated with rituximab and ibrutinib, developed a HL nodular sclerosis variant after three months of therapy for CLL. After achieving a complete remission for HL and ibrutinib cessation because of drug-related cardiotoxicity, the patient relapsed after five months off-therapy and died due to disease progression after two cycles of brentuximab-vedotin. The second case involved an 83-year-old female with a diagnosis of stage-IV CLL treated with rituximab plus bendamustine who developed a HCL eight years later. Pentostatin was unsuccessfully employed as upfront HCL therapy, and the patient was then switched to rituximab while in remission for CLL. In conclusion, Richter’s transformation risk rate might be higher in patients treated with novel targeted therapies, and multiparametric flow cytometry and lymph node biopsy at relapse could help in early identifying small clones. The treatment of predominant neoplasia is mandatory, and disease-specific drugs are administered; however, clinical efficacy might be lower in these patients.

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Section: Discussionsupporting

confidence: 81%

Hodgkin Lymphoma and Hairy Cell Leukemia Arising from Chronic Lymphocytic Leukemia: Case Reports and Literature Review

D’Addona

Giudice

Pezzullo

et al. 2022

JCM

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“…These results, in line with the established role of NOTCH1 signaling in RT [ 237 , 238 ], suggest that constitutive AKT activation may initially amplify NOTCH1 signaling or add additional signals that accelerate transformation. These signals may later further cooperate with upcoming NOTCH1 mutations at later disease stages to increase survival and immune escape [ 239 , 240 ].…”

Section: Other Mechanisms Of Notch1 Activation In Cllsupporting

confidence: 72%

“…Stimulation of the Notch pathway, along with the other main pathways induced by microenvironmental contacts through the BCR and integrins, may therefore be considered one of the hallmark signaling events distinguishing CLL cells from normal B cells that is necessary for CLL pathogenesis, progression, and Richter transformation [ 237 , 238 ]. One significant piece of evidence supporting this perspective is the typically low expression of the CD20 antigen in CLL, which has long been one of the main phenotypic CLL peculiarities recognized in CLL-specific scores [ 241 ], which occurs due to mechanisms related to the activation of the Notch pathway [ 128 , 134 , 175 ].…”

Section: Discussionmentioning

confidence: 99%

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Pozzo

Bittolo

Tissino

et al. 2022

Cancers

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The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.

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“…In addition to TP53 disruption, the other mutations identified in clonally unrelated RS affected genes that are known to be also involved in the pathogenesis of clonally related RS, including mutations of NOTCH1, ATM, MYC, CDKN2A and CCND3 (Figure 1B). 7,[17][18][19] Notably, mutations of genes that are frequently involved in de novo diffuse large B-cell lymphoma (DLBCL) without a previous history of CLL, including KMT2D, EZH2, CREEBP, BCL2, PIM1, were not found in this cohort of clonally unrelated RS. 20,21…”

Section: Analysis Of the Mutational Profile Of Clonally Unrelated Rs ...mentioning

confidence: 81%

“…The molecular pattern of clonally unrelated RS identified in this study might deserve consideration when designing future treatment algorithms of RS. For clonally related RS, expert opinions propose transplant consolidation after the achievement of first remission in transplant‐eligible patients 1,6,19 . Conversely, transplant consolidation is not currently indicated for clonally unrelated RS 1 .…”

Section: Discussionmentioning

confidence: 99%

Clonally unrelated Richter syndrome are truly de novo diffuse large B‐cell lymphomas with a mutational profile reminiscent of clonally related Richter syndrome

et al. 2022

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Richter syndrome (RS) is mostly due to the direct transformation of the chronic lymphocytic leukaemia (CLL) clone, as documented by the same immunoglobulin heavy-chain variable region (IGHV) rearrangement in both CLL and RS cells.In rare cases characterized by a better outcome, the RS clone harbours a different IGHV rearrangement compared to the CLL phase. We investigated the CLL phase of clonally unrelated RS to test whether the RS clone was already identifiable prior to clinicopathologic transformation, albeit undetectable by conventional approaches. CLL cells of eight patients with unrelated RS were subjected to an ultra-deep nextgeneration sequencing (NGS) approach with a sensitivity of 10 −6 . In 7/8 cases, the RS rearrangement was not identified in the CLL phase. In one case, the RS clone was identified at a very low frequency in the CLL phase, conceivably due to the concomitance of CLL sampling and RS diagnosis. Targeted resequencing revealed that clonally unrelated RS carries genetic lesions primarily affecting the TP53, MYC, ATM and NOTCH1 genes. Conversely, mutations frequently involved in de novo diffuse large B-cell lymphoma (DLBCL) without a history of CLL were absent. These results suggest that clonally unrelated RS is a truly de novo lymphoma with a mutational profile reminiscent, at least in part, of clonally related RS.

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Biology and Treatment of Richter Transformation

Cited by 37 publications

References 118 publications

Hodgkin Lymphoma and Hairy Cell Leukemia Arising from Chronic Lymphocytic Leukemia: Case Reports and Literature Review

Hodgkin Lymphoma and Hairy Cell Leukemia Arising from Chronic Lymphocytic Leukemia: Case Reports and Literature Review

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Clonally unrelated Richter syndrome are truly de novo diffuse large B‐cell lymphomas with a mutational profile reminiscent of clonally related Richter syndrome

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