TP53 MUTATIONS, BUT NOT DELETION OF TP53 AND CDKN2A, HAVE INDEPENDENT PROGNOSTIC VALUE IN MANTLE CELL LYMPHOMA TREATED BY THE NORDIC (MCL2 AND MCL3) REGIMEN
(Abstract release date: 05/18/17)
EHA Library. Eskelund C. 06/23/17; 181396; S109
Christian Winther Eskelund
Contributions
Contributions
Abstract
Abstract: S109
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 12:30 - 12:45
Location: Hall B
Background
During the past decades, the outcome of MCL treatment has improved substantially in younger patients. However, the course of disease remains heterogeneous, and there is a need for better stratification of patients with poor responses from those with durable responses. The Nordic trials, MCL2 and MCL3, represent standard-of-care regimens for younger MCL patients.
Aims
Preliminary analyses of diagnostic samples from MCL2 and MCL3, show that TP53 mutations are associated with significantly poorer outcome. Recently, deletions of TP53 and CDKN2A was shown to confer negative impact in a cohort similar to the Nordic.(Delfau-Larue et al, 2015) Thus, in this study we aim to describe the prevalence and impact of deletions of TP53 and CDKN2A in the light of TP53 mutations.
Methods
Fresh frozen DNA from diagnostic bone marrow samples from MCL2 and MCL3 were analyzed. In both trials, patients received intensified first-line induction therapy with alternating courses of R-CHOP and R-hd-Cytarabine and consolidation with high-dose therapy and ASCT. (Geisler et al, 2008; Kolstad et al, 2014). Targeted NGS of ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3 was performed by Ion Torrent Technology. Cut-off for calling a mutation was set to a variant allele frequency >3%. Median coverage was >2700X. Copy Number Variations (CNVs) of TP53 and CDKN2A were measured by droplet digital PCR by commercially available assays, and RPP30 used as a standard control.
Results
We investigated the presence of CDKN2A and TP53 deletions in diagnostic samples from 175 and 157 patients, respectively. Patients were untreated and <66 years (median 58, range 37-65). Fifty-three percent were either MIPI intermediate- or high-risk, 17% had blastoid morphology and 42% had Ki67≥30%, and 83% had bone marrow involvement at diagnosis. After a median follow-up of 9.2 years, median overall (OS), progression-free survival (PFS) and cumulated incidence of relapse (CIR) of all patients were 12.4 and 8.2 and 10.2 years, respectively.
In our mutational analyses (n=147), only TP53 had prognostic impact in multivariate analyses (MVAs). Outcome of the 15 patients (10%) with TP53-mutations was poor with a median OS, PFS and CIR of 1.8, 1.0 and 1.2 years (p<0.0001 for all three outcomes), respectively.
Preliminary data shows deletions of TP53 in 28 patients (18%) and deletion of CDKN2A in 38 (22%). Eight patients carried both deletions. Del-CDKN2A was significantly associated with mutations of TP53, MIPI high risk, blastoid morphology and Ki67>30%. Del-TP53 was associated with Ki67>30%, but no other high risk markers. Altogether, 31 (25%) of 122 patients harbored a deletion and/or mutation in TP53 and 4 (3%) carried both aberrations.
In univariate analyses, del-TP53 was significantly associated with poor OS (p=0.01), but not PFS and CIR, whereas del-CDKN2A was significant for CIR (p=0.02), but not OS and PFS. Patients with both deletions did significantly worse for all three endpoints. In MVA, (including all factors with significance in univariate analyses: MIPI, blastoid morphology, Ki67-index>30%, NOTCH1 mutations, TP53 mutations, del-TP53 and del-CDKN2A) only mutations of TP53 remained a significant predictor of outcome.
Conclusion
Here we evaluate the impact of TP53- and CDKN2A-deletions in the context of TP53 mutations of younger, optimally treated MCL patients. In line with previous reports, both deletions were associated with poorer outcome; however, in multivariate analyses only TP53 mutations was an independent prognostic factor, substantiating its role as a biomarker for response to the standard-of-care immune-chemotherapy.
Session topic: 20. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): P53, mutation analysis, Mantle cell lymphoma, Gene deletion
Abstract: S109
Type: Oral Presentation
Presentation during EHA22: On Friday, June 23, 2017 from 12:30 - 12:45
Location: Hall B
Background
During the past decades, the outcome of MCL treatment has improved substantially in younger patients. However, the course of disease remains heterogeneous, and there is a need for better stratification of patients with poor responses from those with durable responses. The Nordic trials, MCL2 and MCL3, represent standard-of-care regimens for younger MCL patients.
Aims
Preliminary analyses of diagnostic samples from MCL2 and MCL3, show that TP53 mutations are associated with significantly poorer outcome. Recently, deletions of TP53 and CDKN2A was shown to confer negative impact in a cohort similar to the Nordic.(Delfau-Larue et al, 2015) Thus, in this study we aim to describe the prevalence and impact of deletions of TP53 and CDKN2A in the light of TP53 mutations.
Methods
Fresh frozen DNA from diagnostic bone marrow samples from MCL2 and MCL3 were analyzed. In both trials, patients received intensified first-line induction therapy with alternating courses of R-CHOP and R-hd-Cytarabine and consolidation with high-dose therapy and ASCT. (Geisler et al, 2008; Kolstad et al, 2014). Targeted NGS of ATM, CCND1, TP53, KMT2D, NOTCH1, NOTCH2, WHSC1 and BIRC3 was performed by Ion Torrent Technology. Cut-off for calling a mutation was set to a variant allele frequency >3%. Median coverage was >2700X. Copy Number Variations (CNVs) of TP53 and CDKN2A were measured by droplet digital PCR by commercially available assays, and RPP30 used as a standard control.
Results
We investigated the presence of CDKN2A and TP53 deletions in diagnostic samples from 175 and 157 patients, respectively. Patients were untreated and <66 years (median 58, range 37-65). Fifty-three percent were either MIPI intermediate- or high-risk, 17% had blastoid morphology and 42% had Ki67≥30%, and 83% had bone marrow involvement at diagnosis. After a median follow-up of 9.2 years, median overall (OS), progression-free survival (PFS) and cumulated incidence of relapse (CIR) of all patients were 12.4 and 8.2 and 10.2 years, respectively.
In our mutational analyses (n=147), only TP53 had prognostic impact in multivariate analyses (MVAs). Outcome of the 15 patients (10%) with TP53-mutations was poor with a median OS, PFS and CIR of 1.8, 1.0 and 1.2 years (p<0.0001 for all three outcomes), respectively.
Preliminary data shows deletions of TP53 in 28 patients (18%) and deletion of CDKN2A in 38 (22%). Eight patients carried both deletions. Del-CDKN2A was significantly associated with mutations of TP53, MIPI high risk, blastoid morphology and Ki67>30%. Del-TP53 was associated with Ki67>30%, but no other high risk markers. Altogether, 31 (25%) of 122 patients harbored a deletion and/or mutation in TP53 and 4 (3%) carried both aberrations.
In univariate analyses, del-TP53 was significantly associated with poor OS (p=0.01), but not PFS and CIR, whereas del-CDKN2A was significant for CIR (p=0.02), but not OS and PFS. Patients with both deletions did significantly worse for all three endpoints. In MVA, (including all factors with significance in univariate analyses: MIPI, blastoid morphology, Ki67-index>30%, NOTCH1 mutations, TP53 mutations, del-TP53 and del-CDKN2A) only mutations of TP53 remained a significant predictor of outcome.
Conclusion
Here we evaluate the impact of TP53- and CDKN2A-deletions in the context of TP53 mutations of younger, optimally treated MCL patients. In line with previous reports, both deletions were associated with poorer outcome; however, in multivariate analyses only TP53 mutations was an independent prognostic factor, substantiating its role as a biomarker for response to the standard-of-care immune-chemotherapy.
Session topic: 20. Aggressive Non-Hodgkin lymphoma - Clinical
Keyword(s): P53, mutation analysis, Mantle cell lymphoma, Gene deletion
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