https://chronic-lymphocytic-leukaemia-2020.esh.live/
Author
picture Jasmine Chauzeix1, Cédric Pastoret2, Lucie Donaty1, Nathalie Gachard1, Thierry Fest2, Jean Feuillard1, David Rizzo1
1 : Hematology Laboratory and UMR CNRS 7276/INSERM 1262 CRIBL, Centre de Biologie et de Recherche en Santé, Limoges University Hospital Center and University of
Limoges, Limoges, France.
2 : University of Rennes 1, Rennes University Hospital Center, Inserm, MICMAC - UMR_S 1236, F-35000 Rennes, France.
Tumor mutational burden (TMB)
- Definition = number of non synonymous mutations in the cancer genome1
- Originally assessed by whole-genome or whole exome sequencing
- Can be assessed by targeted high throughput sequencing panels with the same informativeness1
- Essentially used in solid cancers
- TMB is low in CLL in comparison to solid cancers
Karyotype complexity in CLL
- karyotype complexity negatively impacts patients’ survival2
INTRODUCTION
150 CLL patients from 2 different hospital centers
- Series 1 (Limoges): 80 patients (46 treatment-naive, 34 at follow-up)
Amplicon library – 70 genes mutated in B lymphomas – 221.6 kb
IonProton®
- Series 2 (Rennes): 70 patients (all treatment-naive)
Amplicon library – 66 genes mutated in hematological neoplasms – 122.2 kb
NextSeq550 ®
METHODS
→TMB, assessed by targeted high throughput sequencing, is increased in previously treated patients
→TMB was associated with unmutated IGHV and cytogenetic complexity.
→With a threshold set at 2 mutations, TMB was a significant prognostic variable to predict TFS independently of the IGHV mutation status and other genetic data
CONCLUSION
1. Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, Huang F, He Y, Sun J, Tabori U, Kennedy M, Lieber DS, Roels S, White J, Otto GA, Ross JS, Garraway L, Miller VA, Stephens PJ, Frampton GM.
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017 Apr 19;9(1):34. doi: 10.1186/s13073-017-0424-2. PMID: 28420421; PMCID: PMC5395719.
2. Jondreville L, Krzisch D, Chapiro E, Nguyen-Khac F. The complex karyotype and chronic lymphocytic leukemia: prognostic value and diagnostic recommendations. Am J Hematol. 2020 Aug 10. doi: 10.1002/ajh.25956. Epub ahead of print. PMID: 32777106.
3. Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-
Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. doi: 10.1182/blood-2012-09-458265. Epub 2012 Dec 13. PMID: 23243274; PMCID:
PMC3578955.
REFERENCES
contact : [email protected]
Tumor Mutational Burden is associated with cytogenetic complexity and detects patients
with evolving Chronic Lymphocytic Leukemia: results of a bicentric study
OBJECTIVES
→ Explore the prognosis value of TMB, assessed by targeted
high throughput sequencing panels like those used in routine
hematology diagnosis
→Compare TMB with other prognosis markers in CLL
RESULTS
Figure 1: TMB of patients from series 1 accordingto treatment history:TMB is higher in patients previously treated
treatment-naive at follow-up
TMB
TMB
mutated IGHV unmutated IGHV
Figure 2: TMB according to IGHV mutational status:TMB is higher in patients unmutated IGHV
0
2
4
6
0
2
4
6
TMB
Very lowrisk
Lowrisk
Intermediaterisk
High risk
Figure 3: TMB of patients according to Rossi’s score:TMB is higher in patients with adverse Rossi’s score3
0
2
4
6
Rossi’s score
TMB
0
2
4
6
Not complex Complex
Karyotype
Figure 4: TMB of patients according to karyotype complexityTMB is higher in patients with complex karyotype
Figure 5: Treatment-free survival (TFS) of untreated patients from series 1 (5A), series 2 (5B) and whole series (5C)
Figure 5B Figure 5CFigure 5A
Multivariate analysis:
Cox multivariate analysis among untreated Binet stage A patients, including all genetic and cytogenetic parameters→ Only the TMB was an independent prognosis marker on TFS (p=0.004)
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