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Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):604-614
Clonal evolution in chronic lymphocytic leukemia is scant in relapsed but accelerated in refractory cases after chemo(immune) therapy
Marc Zapatka,1* Eugen Tausch,2* Selcen Öztürk,1 Deyan Yordanov Yosifov,2,3 Martina Seiffert,1 Thorsten Zenz,4 Christof Schneider,2 Johannes Bloehdorn,2 Hartmut Döhner,2 Daniel Mertens,2,3 Peter Lichter1 and Stephan Stilgenbauer2
1Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany; 2Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany; 3Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany and 4University Hospital, University of Zürich, Zürich, Switzerland
*MZ and ET contributed equally as co-first authors.
ABSTRACT
Clonal evolution is involved in the progression of chronic lympho- cytic leukemia (CLL). In order to link evolutionary patterns to dif- ferent disease courses, we performed a long-term longitudinal mutation profiling study of CLL patients. Tracking somatic mutations and their changes in allele frequency over time and assessing the under- lying cancer cell fraction revealed highly distinct evolutionary patterns. Surprisingly, in long-term stable disease and in relapse after long-lasting clinical response to treatment, clonal shifts are minor. In contrast, in refractory disease major clonal shifts occur although there is little impact on leukemia cell counts. As this striking pattern in refractory cases is not linked to a strong contribution of known CLL driver genes, the evolution is mostly driven by treatment-induced selection of sub-clones, underlin- ing the need for novel, non-genotoxic treatment regimens.
Introduction
Cancer can be conceptualized as an evolutionary process within a given organ- ism.1,2 By increasing the fitness of cancer cells, mutations enable sub-clones to out- compete non-malignant cells and less adapted cancer cell clones. Furthermore, clon- al evolution allows the selection of cell populations that are resistant to therapy or responsible for disease recurrence. For some tumor entities like acute myeloid leukemia (AML), the concept of cancer initiating cells seems to account for tumor relapses without further genetic evolution. For other malignancies however, it is more likely that additional mutations play a crucial role in tumor recurrence. This is also true for chronic lymphocytic leukemia (CLL), where progression and clonal evolution have been analyzed in the context of treatment induced genetic changes.3,4
Clinically, CLL is characterized by a highly variable course. The survival time of patients varies between months and decades. Often patients remain untreated for many years until clinical symptoms require therapeutic intervention.5 Despite high rates of initial treatment response, a major clinical challenge is the occurrence of refractory disease that does not respond to treatment. Refractory cases are often characterized by a deletion and/or a mutation in the tumor suppressor gene TP53 located on the short arm of chromosome 17 (del17p/TP53mut). Although a number of recurrently mutated genes were identified in CLL that are of prognostic rele- vance4,6-9 del17p/TP53mut remains the strongest adverse prognostic factor for pro- gression-free and overall survival in CLL.4,10,11 The incidence of mutated or deleted TP53 is below 3% in Binet A stage CLL representing cases with good prognosis or in the pre-malignant monoclonal B-cell lymphocytosis (MBL) state, but increases to 12% at time of first treatment initiation, and to more than 37% in chemotherapy refractory cohorts.8,12,13 Despite this increase in cases with mutated or deleted TP53 at later disease stages, clonal evolution has been considered rare in CLL.
Chronic Lymphocytic Leukemia
Correspondence:
PETER LICHTER
Peter.Lichter@dkfz-heidelberg.de
STEPHAN STILGENBAUER
Stephan.Stilgenbauer@uniklinik-ulm.de
Received: July 7, 2020. Accepted: February 26, 2021. Pre-published: March 11, 2021.
https://doi.org/10.3324/haematol.2020.265777 ©2022 Ferrata Storti Foundation
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