Dissecting clonal hematopoiesis in the myeloid compartment of chronic lymphocytic leukemia and Richter transformation

The clinical and biological significance of clonal hematopoiesis (CH) has not been investigated in the myeloid compartment of chronic lymphocytic leukemia (CLL). By studying 488 newly diagnosed CLL through CAPP-seq using a 28-gene panel on granulocyte genomic DNA (gDNA), CH occurred in 231 (47.3%) patients. Cell sorting of cases that never developed Richter transformation (RT) confirmed that CH mutations, including CH-related <i>TP53</i> mutations, were restricted to the myelomonocytic compartment and absent in CLL cells, as also documented by single-cell DNA sequencing. CH associated with shorter overall survival (OS) (hazard ratio [HR] 1.36, 95% CI 1.04-1.77, P = 0.023); specifically, <i>TET2</i> mutations independently predicted inferior OS (HR 1.62, 95% CI 1.15-2.28, P = 0.01) after adjusting for age and for CLL-related prognostic biomarkers, namely IGHV and <i>TP53</i> status. Regarding therapy-related toxicities, CH correlated with a higher incidence of Grade ≥ 3 neutropenia (P = 0.004) after venetoclax-based regimens. Sequential samples (<i>n</i> = 57) analysis showed that Bruton tyrosine kinase (BTK) and BCL2 inhibitors do not induce CH expansion, which was instead driven by chemotherapy. CH is significantly associated with a higher risk of second hematological malignancies only in chemo-exposed patients. Single-cell RNA sequencing of seven CH+ and six CH- CLL revealed that the T-cell compartment of CH+ patients exhibits a less exhausted phenotype, documented by lower expression of TOX, the master regulator of T-cell exhaustion, and a higher pro-inflammatory profile. CH also influenced RT, since CH <i>ASXL1</i> mutations independently associated with higher RT risk (HR 11.19, 95% CI 4.09-30.62, P < 0.001). Overall, CH in CLL impacts survival, therapeutic toxicity, and transformation risk while also influencing the T-cell immune compartment.

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Journal
HemaSphere
Published
2026-02-01
DOI
https://doi.org/10.1002/hem3.70322
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
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0.00

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article

Dissecting clonal hematopoiesis in the myeloid compartment of chronic lymphocytic leukemia and Richter transformation

A. Mokhtar Mahmoud, Lodovico Terzi di Bergamo, Maura Nicolosi, Roberto Chiarle et al.
HemaSphere
Chronic Lymphocytic Leukemia Research
article

Dissecting clonal hematopoiesis in the myeloid compartment of chronic lymphocytic leukemia and Richter transformation

A. Mokhtar Mahmoud, Lodovico Terzi di Bergamo, Maura Nicolosi, Roberto Chiarle, Valeria Caneparo, Luca Vincenzo Cappelli, C. Deambrogi, A. Zucchetto, Silvia Rasi, Matin Salehi, R. Foa, R. Moia, Annalisa Gaglio, Sreekar Kogila, Laura Fumagalli, Riccardo Dondolin, Valentina Griggio, Francesca Perutelli, Samir Mouhssine, Deborah Cardinali, Joseph Ghanej, Pileri Sa, L. Trentin, Ilaria Romano, Matteo Bellia, Milena Lazzaro, Valter Gattei, Luca Cividini, Francesca Maiellaro, Mohammad Reshad Nawabi, Candida Vitale, Lydia Scarfò, Nawar Maher, Davide Rossi, Paolo Ghia, Gianluca Gaidano, Bashar Al Deeban, Chiara Cosentino, Marta Coscia, Mohammad Almasri, Fabio Iannelli, Jana Nabki, Ilaria Del Giudice, Andrea Visentin, Eleonora Secomandi, Elisa Albi
article en

Abstract

The clinical and biological significance of clonal hematopoiesis (CH) has not been investigated in the myeloid compartment of chronic lymphocytic leukemia (CLL). By studying 488 newly diagnosed CLL through CAPP-seq using a 28-gene panel on granulocyte genomic DNA (gDNA), CH occurred in 231 (47.3%) patients. Cell sorting of cases that never developed Richter transformation (RT) confirmed that CH mutations, including CH-related <i>TP53</i> mutations, were restricted to the myelomonocytic compartment and absent in CLL cells, as also documented by single-cell DNA sequencing. CH associated with shorter overall survival (OS) (hazard ratio [HR] 1.36, 95% CI 1.04-1.77, P = 0.023); specifically, <i>TET2</i> mutations independently predicted inferior OS (HR 1.62, 95% CI 1.15-2.28, P = 0.01) after adjusting for age and for CLL-related prognostic biomarkers, namely IGHV and <i>TP53</i> status. Regarding therapy-related toxicities, CH correlated with a higher incidence of Grade ≥ 3 neutropenia (P = 0.004) after venetoclax-based regimens. Sequential samples (<i>n</i> = 57) analysis showed that Bruton tyrosine kinase (BTK) and BCL2 inhibitors do not induce CH expansion, which was instead driven by chemotherapy. CH is significantly associated with a higher risk of second hematological malignancies only in chemo-exposed patients. Single-cell RNA sequencing of seven CH+ and six CH- CLL revealed that the T-cell compartment of CH+ patients exhibits a less exhausted phenotype, documented by lower expression of TOX, the master regulator of T-cell exhaustion, and a higher pro-inflammatory profile. CH also influenced RT, since CH <i>ASXL1</i> mutations independently associated with higher RT risk (HR 11.19, 95% CI 4.09-30.62, P < 0.001). Overall, CH in CLL impacts survival, therapeutic toxicity, and transformation risk while also influencing the T-cell immune compartment.

HemaSphereVol. 10(2)
University of Insubria (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Boston Children's Hospital (US), University of Padua (IT), Vita-Salute San Raffaele University (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Institute of Oncology Research (CH), Centro di Riferimento Oncologico (IT), IRCCS Ospedale San Raffaele (IT), Azienda Ospedale - Università Padova (IT), University of Turin (IT), European Institute of Oncology (IT), Sapienza University of Rome (IT)
Associazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 54%
Chronic Lymphocytic Leukemia Research
DOIOpen Access PDFOpenAlex
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