Chronic lymphocytic leukemia patient-derived xenografts recapitulate clonal evolution to Richter transformation DOI Creative Commons
Heribert Playà-Albinyana, Fabián Arenas, Romina Royo

et al.

Leukemia, Journal Year: 2023, Volume and Issue: 38(3), P. 557 - 569

Published: Nov. 28, 2023

Abstract Chronic lymphocytic leukemia (CLL) is a B-cell neoplasm with heterogeneous clinical behavior. In 5–10% of patients the disease transforms into diffuse large-B cell lymphoma known as Richter transformation (RT), which associated dismal prognosis. Here, we aimed to establish patient-derived xenograft (PDX) models study molecular features and evolution CLL RT. We generated two PDXs by injecting (PDX12) RT (PDX19) cells immunocompromised NSG mice. Both were morphologically phenotypically similar Whole-genome sequencing analysis at different time points PDX revealed genomic landscape tumors from both uncovered an unprecedented subclonal heterogeneity clonal during generation. PDX12, transformed expanded very small subclone already present stage. Transcriptomic showed high oxidative phosphorylation (OXPHOS) low receptor (BCR) signaling in patients. IACS-010759, OXPHOS inhibitor, reduced proliferation, circumvented resistance venetoclax. summary, have new RT-PDX models, one them that mimicked uncovering intrinsic therapeutical value.

Language: Английский

Richter syndrome: Novel insights into the biology of transformation DOI
Erin M. Parry, Elisa ten Hacken, Catherine J. Wu

et al.

Blood, Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 9, 2023

Language: Английский

Citations

23
NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia DOI Creative Commons
Alice Bonato, Supriya Chakraborty, Riccardo Bomben

et al.

Leukemia, Journal Year: 2024, Volume and Issue: 38(7), P. 1511 - 1521

Published: March 15, 2024

Abstract Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies have been associated with accelerated disease progression inferior responses to chemotherapy. Using vitro vivo murine models primary patient samples, we now show that NFKBIE-mutated CLL cells selected by microenvironmental signals activate pathway induce alterations within tumor microenvironment can allow immune escape, including expansion of CD8+ T-cells an exhausted phenotype increased PD-L1 expression on malignant B-cells. Consistent latter observations, find exhaustion markers from patients CLL. In addition, display selective resistance ibrutinib report outcomes treatment patients. These findings suggest NFKBIE contribute through multiple mechanisms, a bidirectional crosstalk reduced sensitivity BTK treatment.

Language: Английский

Citations

9
ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome DOI Creative Commons
Erin M. Parry, Camilla K. Lemvigh, Stephanie Deng

et al.

Cancer Cell, Journal Year: 2023, Volume and Issue: 41(10), P. 1803 - 1816.e8

Published: Sept. 21, 2023

Language: Английский

Citations

21
Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial DOI Creative Commons
Othman Al‐Sawaf, Rudy Ligtvoet, Sandra Robrecht

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 30(1), P. 240 - 248

Published: Dec. 9, 2023

In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated poor response to chemotherapy and short survival. We initiated international, investigator-initiated, prospective, open-label phase 2 study in which RT received a combination PD-1 inhibitor tislelizumab plus BTK zanubrutinib for 12 cycles. Patients responding treatment underwent maintenance both agents. The primary end point was overall rate after six Of 59 enrolled patients, 48 at least two cycles comprised analysis population according protocol. median observation time 13.9 months, age 67 (range 45-82) years. Ten (20.8%) had previous RT-directed therapy. total, 28 out responded induction therapy 58.3% (95% confidence interval (CI) 43.2-72.4), including 9 (18.8%) complete reponse 19 (39.6%) partial response, meeting study's by rejecting predefined null hypothesis 40% (P = 0.008). Secondary points included duration progression-free survival not reached, 10.0 months CI 3.8-16.3). Median reached 12-month 74.7% 58.4-91.0). most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) hematological toxicities (11.4%). These data suggest combined checkpoint inhibition effective well-tolerated strategy RT. ClinicalTrials.gov Identifier: NCT04271956 .

Language: Английский

Citations

19
Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study DOI
William G. Wierda, Nirav N. Shah, Chan Y. Cheah

et al.

The Lancet Haematology, Journal Year: 2024, Volume and Issue: 11(9), P. e682 - e692

Published: July 18, 2024

Language: Английский

Citations

8
The molecular map of CLL and Richter's syndrome DOI Creative Commons
Amit Sud, Erin M. Parry, Catherine J. Wu

et al.

Seminars in Hematology, Journal Year: 2024, Volume and Issue: 61(2), P. 73 - 82

Published: Jan. 23, 2024

Clonal expansion of B-cells, from the early stages monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases Richter's syndrome (RS) provides a comprehensive model cancer evolution, notable for marked morphological transformation distinct clinical phenotypes. High-throughput sequencing large cohorts patients single-cell studies have generated molecular map CLL more recently, RS, yielding fundamental insights into these diseases clonal evolution. A selection driver genes been functionally interrogated yield novel biology . Such findings potential impact patient care risk stratification, treatment drug discovery. However this remains incomplete, with extant questions concerning origin clone, role TME, inter- intra-compartmental heterogeneity therapeutic resistance mechanisms. Through application multi-modal technologies across tissues, disease states contexts, can now be addressed answers holding great promise generating translatable knowledge improve care.

Language: Английский

Citations

5
Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation DOI
Nicoletta Cieri,

Nidhi Hookeri,

Kari Stromhaug

et al.

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 21, 2024

Language: Английский

Citations

5
Allogeneic hematopoietic stem-cell transplantation for patients with Richter transformation: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT DOI
Romain Guièze,

Diderik-Jan Eikema,

Linda Köster

et al.

Bone Marrow Transplantation, Journal Year: 2024, Volume and Issue: 59(7), P. 950 - 956

Published: March 19, 2024

Language: Английский

Citations

4
Understanding splenic B‐cell lymphoma/leukaemia with prominent nucleoli: Diagnosis, underpinnings for disease classification and future directions DOI
Kikkeri N. Naresh

British Journal of Haematology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Summary The 5th edition of the WHO classification haematolymphoid tumours (WHO‐HAEM5) introduced a new category, splenic B‐cell lymphoma/leukaemia with prominent nucleoli (SBLPN). diagnostic entity prolymphocytic leukaemia (B‐PLL) has been discontinued and category hairy cell variant (HCLv) conceptually reframed. B‐PLL HCLv diagnoses were uncommon. Overlap existed between other indolent lymphomas like chronic lymphocytic leukaemia/small lymphoma (CLL/SLL). lacked consistent cytomorphological, immunophenotypic genetic features. To address these issues, WHO‐HAEM5 SBLPN to serve as temporary holding ground for entities that do not neatly fit into existing classification. Cases previously classified CD5‐negative fall under category. Some marginal zone diffuse red pulp small cases higher number medium or large nucleolated B cells would also be WHO‐HAEM5. This review explores rationale discontinuing diagnoses. It then examines concept SBLPN, offers practical guidance diagnosis discusses future directions in classifying lymphomas.

Language: Английский

Citations

4
In VivoModeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities DOI
Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin

et al.

Blood Cancer Discovery, Journal Year: 2022, Volume and Issue: 4(2), P. 150 - 169

Published: Dec. 5, 2022

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing recurrent CLL loss-of-function drivers mice and recapitulated process transformation from indolent into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories 64 carrying diverse combinatorial gene assortments revealed coselection mutations Trp53, Mga, Chd2 dual impact clonal Mga/Chd2 on E2F/MYC interferon signaling dysregulation. Comparative human murine RS analyses demonstrated tonic PI3K as a key feature transformed disease, with constitutive activation AKT S6 kinases, downmodulation PTEN phosphatase, convergent MYC/PI3K transcriptional programs underlying enhanced sensitivity MYC/mTOR/PI3K inhibition. This robust experimental system presents unique framework study lymphoid biology therapy.Mouse models reflective complexity tumors few, including those able recapitulate histologies. Herein, we model editing, providing insight pathophysiology therapeutic vulnerabilities disease. article is highlighted In Issue feature, p. 101.

Language: Английский

Citations

17