Screening for TP53 Mutations Identifies Chronic Lymphocytic Leukemia Patients with Rapid Disease Progression.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 490-490 ◽  
Author(s):  
Frank Dicker ◽  
Hannes Herholz ◽  
Susanne Schnittger ◽  
Aki Nakao ◽  
Nancy Patten ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Clinical Course ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Time To Progression ◽  
Single Nucleotide ◽  
Tp53 Mutations ◽  
The Poor

Abstract Screening for cytogenetic aberrations with a selected panel of FISH probes has identified important prognostic subgroups in chronic lymphocytic leukemia (CLL). Good prognosis CLL patients with deletions of the long arm of chromosome 13 (del13q) as sole aberration are opposed by patients with deletions of the short arm of chromosome 17 (del17p). The tumor suppressor gene TP53 is located at 17p13 and loss of TP53 is hypothesized to be at least partially responsible for the poor prognosis of del17p CLL patients. However, it is not clear, if the loss of other genes in the deleted region contributes to the poor prognosis. In addition, the degree of overlap between the patient populations defined by del17p and TP53 mutation is only poorly defined. Therefore, we characterized peripheral blood or bone marrow samples of 193 CLL patients by FISH analysis and screened for TP53 mutations by two methods, i.e. by denaturing high performance liquid chromatography (dHPLC) and by a microarray-based resequencing assay, the AmpliChip p53 Test. PCR products of exons 3–9 of TP53 were screened by dHPLC and aberrant fragments were analyzed by direct sequencing, whereas the entire coding region including the splice sites of exons 2–11 were analyzed with the AmpliChip p53 Test. The overall incidence of TP53 mutations by both methods was 13.5% (26/193), whereas the incidence of del17p by FISH was 9.3% (18/193). Interestingly, 17 out the 18 del17p samples carried a TP53 mutation suggesting that loss of TP53 does indeed play a pivotal role in the poor prognosis of del17p. At least 9 samples carried a TP53 mutation only. The AmpliChip p53 Test detected 32 mutations in 25 patients compared to 24 mutations detected in 20 patients by dHPLC/direct sequencing. The AmpliChip p53 Test, which is designed to detect single nucleotide substitutions and single nucleotide deletions, did not detect 3 mutations (1 1-bp deletion, 1 4-bp deletions, 1 single nucleotide insertion). The method of dHPLC followed by direct sequencing did not call 10 single nucleotide mutations. Of these, 1 mutation was located in exon 10 not included in the dHPLC screening. The remaining 9 mutations were detected by dHPLC analysis, but failed to be called by direct sequencing. The clinical course of patients with TP53 aberrations (n=20) (del17p and/or TP53 mutation) was compared to 113 patients lacking these abnormalities. Patients with TP53 aberration had a highly significantly decreased time to progression compared to patients without TP53 aberration (p<0.001, median 13.2 vs. 64.4 months). This difference remained significant when analysis was restricted to patient samples without prior therapy (p<0.001, median 9.2 (n=13) vs. 70.6 months (n=101)). As FISH analysis for del17p is the standard approach to detect TP53 aberrations, we compared the clinical course of patients with del17p (n=8) to patients with TP53 mutation (without del17p) (n=7) vs patients without TP53 aberration (n=113). This analysis resulted in a median time to progression of 9.2 vs 22.4 vs 63.4 month, respectively (p<0.001). The data of the present analysis suggest that TP53 mutation might be one of the factors conferring poor prognosis to CLL patients. Likewise, we identified 9 samples (4.7%) with TP53 mutation alone with poor clinical course that would have escaped detection by FISH analysis.

Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3322-3329 ◽  
Author(s):  
Thorsten Zenz ◽  
Alexander Kröber ◽  
Katrin Scherer ◽  
Sonja Häbe ◽  
Andreas Bühler ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Clone Size ◽  
Tp53 Mutations ◽  
Long Term Follow Up ◽  
Serial Samples

AbstractThe exact prognostic role of TP53 mutations (without 17p deletion) and any impact of the deletion without TP53 mutation in CLL are unclear. We studied 126 well-characterized CLL patients by direct sequencing and DHPLC to detect TP53 mutations (exons 2-11). Most patients with 17p deletions also had TP53 mutations (81%). Mutations in the absence of 17p deletions were found in 4.5%. We found a shorter survival for patients with TP53 mutation (n = 18; P = .002), which was more pronounced when analyzed from the time point of mutation detection (6.8 vs 69 months, P < .001). The survival was equally poor for patients with deletion 17p plus TP53 mutation (7.6 months, n = 13), TP53 mutation only (5.5 months, n = 5), and 17p deletion only (5.4 months, n = 3). The prognostic impact of TP53 mutation (HR 3.71) was shown to be independent of stage, VH status, and 11q and 17p deletion in multivariate analysis. Serial samples showed evidence of clonal evolution and increasing clone size during chemotherapy, suggesting that there may be patients where this treatment is potentially harmful. TP53 mutations are associated with poor sur-vival once they occur in CLL. The de-monstration of clonal evolution under selective pressure supports the biologic significance of TP53 mutations in CLL.

scholarly journals Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3283-3283
Author(s):  
Barbara Kantorova ◽  
Jitka Malcikova ◽  
Veronika Navrkalova ◽  
Jana Smardova ◽  
Kamila Brazdilova ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
The Other ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Time To First Treatment ◽  
Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

scholarly journals Single Cell Analysis Proves the Coexistence of NOTCH1 and TP53 Mutations within the Same Cancer Cells in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2913-2913
Author(s):  
Barbara Kantorova ◽  
Jitka Malcikova ◽  
Kamila Brazdilova ◽  
Marek Borsky ◽  
Karla Plevova ◽  
...  
Keyword(s):  
Single Cell ◽  
Tp53 Mutation ◽  
Single Cell Analysis ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
Lymphocytic Leukemia ◽  
Cell Analysis ◽  
Tp53 Mutations ◽  
First Time ◽  
Clonal Composition

Abstract Introduction Mutations in NOTCH1 and especially TP53 genes represent potent drivers of chronic lymphocytic leukemia (CLL) progression and chemo-refractoriness. Although a coexistence of these mutations was reported in CLL, a molecular basis of this phenomenon has not been described yet. To clarify this issue, we performed a detailed analysis of CLL patients with parallel NOTCH1 and TP53 mutations including single cancer cell examination. Methods TP53 mutations were determined based on FASAY analysis coupled with direct sequencing. In a collected cohort of 111 TP53 -mutated patients a presence of hot spot c.7544_7545delCT NOTCH1 mutation was assessed using direct gDNA sequencing. In NOTCH1 -TP53 -mutated patients with available material, the mutations' coexistence was tested in single flow-sorted CD19+ cells (cancer cell proportion > 80 %) using multiplex PCR followed by direct sequencing. Results The NOTCH1 mutation was detected in 19/111 (17 %) of the TP53 -mutated patients. Eleven of the NOTCH1-TP53 -mutated patients carried single TP53 mutation; multiple TP53 mutations were detected in 8 of them. Based on gDNA sequencing, the NOTCH1 and TP53 mutation coexistence in the same cancer cells was evident in 4/19 of the NOTCH1-TP53-mutated patients, as at least one of the gene mutations occurred in 100 % of the DNA. In the remaining 15 NOTCH1-TP53 -mutated patients the clonal composition was not possible to assess using sequencing data only and therefore a single cell analysis was performed in 8 of them with available material. Remarkably, irrespective of the mutation proportion, in all of these patients the NOTCH1 mutation was always present together with at least one of the detected TP53 mutations. Considering both the DNA sequencing and single cell analysis data, the 12 patientswith proven NOTCH1-TP53 mutation coexistence might be stratified into three groups with different clonal composition: i) patients with NOTCH1 and single TP53 mutations showing a comparable mutation proportion (n = 3), in which both gene mutations were always detected in the same cells and never occurred separately; ii) patients with either NOTCH1 or TP53 mutation predominance (n = 6), in which the predominant mutation was present separately as well as in combination with the coexisting mutation(s) in individual cells; iii) patients with NOTCH1 and multiple TP53 mutations showing different mutation proportion (n = 3), in which NOTCH1 mutation was present together with one of the detected TP53 mutations in the same cells, while the other TP53 mutations occurred separately. In two of the NOTCH1-TP53 -mutated patients who received intensive chemo-immunotherapy, the consecutive samples were available for single cell analysis. In one of these patients only single TP53 mutation was detected at first time point. In relapse after rituximab-dexamethasone treatment the clone carrying the original TP53 mutation expanded in parallel with another NOTCH1-TP53-mutated clone. Different situation was noticed in the second patient, in which the NOTCH1-TP53-mutated clone detected at first time point diminished after alemtuzumab treatment, while another TP53-mutated-NOTCH1-wild-type clone expanded in relapse. Conclusion We have shown that in NOTCH1-TP53 -mutated patients the mutations often coexist in the same CLL cells. These patients exhibit a considerable clonal heterogeneity that may be further influenced by chemo-immunotherapy. This study was supported by IGA NT/13493 and NT/13519, MUNI/A/1180/2014, CZ.1.05/1.1.00/02.0068. Disclosures Mayer: Janssen: Research Funding.

Loss or Mutation of TP53 Is Highly Associated with Complex Aberrant Karyotype and Chromosomal Translocations in Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2087-2087
Author(s):  
Hannes Herholz ◽  
Claudia Schoch ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tp53 Mutation ◽  
Direct Sequencing ◽  
Lymphocytic Leukemia ◽  
Chromosomal Translocations ◽  
Entire Group ◽  
Unbalanced Translocation ◽  
Tp53 Mutations ◽  
Cytogenetic Aberrations ◽  
Balanced Translocations

Abstract In chronic lymphocytic leukemia (CLL) cytogenetic aberrations such as del(17p) and del(11q) predict inferior outcome. In addition, complex aberrant karyotypes as well as chromosomal translocations as defined by metaphase cytogenetics were suggested as poor prognostic markers for overall survival. We screened 194 consecutive CLL patients for del(17p)/TP53-deletion by fluorescence in situ hybridization (FISH) and for TP53-mutations by denaturing high performance liquid chromatography (DHPLC) and subsequent direct sequencing of aberrant fragments. In addition 160 of these CLL patients were analyzed by classical metaphase cytogenetics to determine the incidence of TP53-aberration in different cytogenetic subgroups. Interphase FISH on 194 samples detected TP53-deletions in 9.3% (n=18) of cases. In parallel, exons 3–9 of the TP53 gene were screened by DHPLC and an aberrant pattern was detected in 9.8% (n=19) of cases. TP53-mutations were confirmed and further characterized by direct sequencing in 16 of the 19 cases. The residual 3 samples had an aberrant pattern in DHPLC for the amplicon of exons 8–9 which pointed to a small population of TP53-aberrant cells which was beyond the detection limit of sequencing. 16 of 18 (89%) cases with TP53-deletion were accompanied by a TP53-mutation affecting the residual allele. 3 samples with TP53-mutations had no deletion of one TP53 allele. Therefore, the overall incidence of TP53-aberrations was 10.8 % (21/194) with a significant association of TP53-deletion and TP53-mutation (p<0.0001). Metaphase cytogenetics was performed on 160 CLL samples. A complex aberrant karyotype defined by ≥ 3 aberrations was identified in 14% of samples (22/160). The incidence of TP53-aberrations in this cytogenetic subgroup was 50% (11/22) and therefore significantly higher than in other cytogenetic subgroups (p<0.0001). Among 160 samples with cytogenetic analysis 49 (31%) exhibited translocations. We divided these translocations into subgroups with karyotypes carrying balanced translocations only (n=18), carrying unbalanced translocations only (n=20) as well as karyotypes with both balanced and unbalanced translocations (n=11). Within the entire group of translocations the incidence of TP53-aberration was 27% (13/49). The incidence of TP53-aberrations was 5.5% (1/18) in the group with only balanced translocations, 40% (8/20) in the group with only unbalanced translocations and 36% (4/11) where balanced and unbalanced translocation occurred in combination. When the latter two groups with unbalanced translocations were combined TP53-aberration occurred in 39% (12/31) of cases. Altogether the association of TP53-aberration with translocations was strong (p<0.0001) especially with unbalanced translocations (p<0.0001) whereas no coherency with balanced translocations could be demonstrated (p>0.05). Furthermore, translocations were detected in 91% (20/22) and unbalanced translocations in 82% (18/22) of complex karyotypes. The association of translocations, in particular unbalanced translocation with complex aberrant karyotype was significant (for both p<0.0001). In conclusion: Loss of TP53 and TP53 mutations occur with a frequency of 9.3% and 9.8%, respectively and are significantly associated. A highly significant association of TP53-aberrations with complex aberrant karyotypes and unbalanced translocations was observed. We hypothesize that TP53-aberrations might contribute to genetic instability leading to accumulation of cytogenetic aberrations especially unbalanced translocations.

Utilization of Targeted Exome Sequencing to Determine Implications of TP53 Mutation Status in Relation to 17p Deletion in Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3287-3287
Author(s):  
Ateefa Chaudhury ◽  
Julio C Chavez ◽  
Javier Pinilla-Ibarz
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Exome Sequencing ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Cancer Center ◽  
Tp53 Mutations ◽  
Targeted Exome Sequencing ◽  
The Impact

Abstract Background: Advances in molecular genetics have changed the risk stratification and treatment of patients with Chronic Lymphocytic Leukemia (CLL). Previous studies have shown the worst patient outcomes associated with 17p deletion from diminished overall and progression free survival, in addition to lack of response to conventional Fludarabine based chemotherapy regimens. More recently, analyses of the role of TP53 mutation utilizing next generation sequencing (NGS) in CLL patients has shown that it may also be associated with poor prognosis and similar outcomes to those patients with 17p deletion. This study seeks to characterize the role of TP53 mutation and 17p deletion with overall survival (OS) of CLL patients treated at H. Lee Moffitt Cancer Center who underwent Targeted Exome Sequencing (TES). Methods: We utilized the Total Cancer Care/H. Lee Moffitt Cancer Center (MCC) database containing 844 CLL patients of diverse ethnic backgrounds and long survival follow up to determine the rates and outcomes of 17p deletion within our population. A subset of 93 patients treated between 2004 and 2010 at MCC were randomly chosen for TES. Bone marrow and/or peripheral blood samples were subjected to genomic capture and massive parallel sequencing of 1,321 cancer-related genes. Sequences were aligned to the hs37d5 human reference. Insertion/deletion realignment, quality score recalibration, and variant identification were performed with the Genome Analysis ToolKit (GATK). Sequence variants for TP53 and 17p deletion were annotated with ANNOVAR. Alignments using BWA and Stampy were manually inspected with Samtools View. The primary objective was to determine OS stratified into four groups: 1) TP53 positive/17p deletion positive (tp53+/17pdel+), 2) TP53 negative/17p deletion positive (tp53-/17pdel+), 3) TP53 positive/17p deletion negative (tp53+/17pdel-), and lastly 4) TP53 negative/17p deletion negative (tp53-/17pdel-). Results: Analysis of patients with genetic data available in our larger population of CLL patients at MCC (n=844), revealed the median OS of patients with 17pdel+ (n=46) was 6 years vs. 13 years for 17pdel- patients (Figure 1, p<0.001). These results were comparable to our CLL patients that underwent TES. Among patients who underwent TES (n=93), the median age was 58 (34-87) years and the male/female ratio was 63/30. Sixteen patients had Rai Stage III/IV disease (17.3%). ZAP70 and CD38 were positive in 41 (44.1%) and 11 patients (11.8%), respectively. Recurrent CLL mutations by FISH showed 13qdel in 54 (58.1%), 11qdel in 19 (20.4%), trisomy 12 in 18 (19.4%), and 17pdel in 12 (12.9%) cases. By TES, TP53 mutation was the most frequent mutation and detected in 18/93 (19.4%) of patients. The median OS for 17pdel+ vs. 17pdel- in this population were 9.6 and 14 years, respectively (p=0.023). When patients were divided by subgroups the frequencies were as follows: tp53+/17p+ in 10 (10.8%), tp53-/17p+ in 2 (2.2%), tp53+/17p- in 8 (8.6%), and tp53-/17p- in 73 (78.5%). The median OS for patients with tp53+/17pdel+, tp53+/17pdel-, and tp53-/17pdel- were 2, 9, and 13 years, respectively (Figure 2, p=0.028). Due to the small number in the tp53-/17pdel+ subgroup, the median OS could not be determined. Conclusion: The impact of TP53 mutations detected by NGS in CLL patients is still under investigation. TP53 mutation and 17p deletion are associated with a very poor prognosis. The impact of TP53 mutation in the absence of 17p deletion is not well understood. Within our study, our findings clearly show the 84.6% reduction in OS (11 years) of tp53+/17p+ patients when compared to tp53-/17pdel- patients. TP53 mutation in the absence of 17p deletion did reduce OS by 4 years (30.8%) when compared to patients who lack the 17p deletion or TP53 mutation. TP53 mutation does appear to impact and shorten OS most strikingly in the presence of 17p deletion, suggesting that 17p deletion may play a greater role in prognosis than TP53 alone. Larger number of patients will be needed in order to confirm these findings and to determine the impact of 17p deletion in patients lacking TP53 mutations. Further analyses of CLL patients utilizing NGS technologies and functional analyses to determine if these mutations fully inactivate TP53 will need to be performed to help further elucidate the role of TP53 mutation in patients with high-risk CLL. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4116-4116
Author(s):  
Anna Dodero ◽  
Anna Guidetti ◽  
Fabrizio Marino ◽  
Cristiana Carniti ◽  
Stefania Banfi ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Tp53 Mutation ◽  
Advisory Committees ◽  
Tp53 Mutations ◽  
Travel Costs ◽  
Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

scholarly journals The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3021-3021
Author(s):  
Gregory Lazarian ◽  
Floriane Theves ◽  
Myriam Hormi ◽  
Virginie Eclache ◽  
Stéphanie Poulain ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Snp Analysis ◽  
Advisory Committees ◽  
Exon 2 ◽  
Tp53 Mutations ◽  
Mutational Status

TP53 aberrations, including somatic mutations of TP53 gene or 17p deletion leading to the loss of the TP53 locus, are a major predictive factor of resistance to fludarabin based chemotherapy in chronic lymphocytic leukemia (CLL) and remain an adverse prognostic factor in the chemofree era. Therefore, detection of TP53 alteration before each new line of treatment is required for theranostic stratification. In order to better characterize the distribution and combination of the TP53 variants in CLL, we collected the TP53 sequencing data of 343 patients harboring TP53 mutations from centers of the French Innovative Leukemia Organization-CLL (FILO) and established a large data base of 573 TP53 mutations. Mutations were identified through NGS sequencing (covering exon 2 to 11) allowing the detection of low frequency variants down to 1% VAF. Several distinct low VAF mutations were orthogonally confirmed by digital PCR. TP53 variants were analyzed through UMD_TP53 data gathering 90 000 TP53 mutations from all type of cancers. IGHV mutational status and FISH analysis were available for 224 and 176 patients respectively. Using ACMG criteria from the UMD_TP53 database, we confirmed that 523 could be classified as pathogenic, 42 were likely pathogenic and 8 were VUS (Variants of Unknown Significance). As expected, the mutation distribution along the p53 protein exhibited a clustering of variants in the DNA binding domain of the protein. We also confirmed the presence of a specific hotspot at codon 234 (6%) which is noticeable in other CLL cohorts but absent in solid tumors. 431 TP53 variants led to the expression of a mutant protein whereas the remaining 142 led a TP53 null phenotype. For 8 patients without 17p deletion and a mutation VAF larger than 50%, SNP analysis indicate that these tumors had a copy number neutral loss of heterozygosis at 17p with a duplication of the mutant allele leading to homozygous mutations of TP53. When focusing on the allele burden of TP53 mutations, 264/573 (46%) variants had an allele frequency <10%. Even if they were predominantly found in polymutated cases, presence of only low VAF (<10%) mutations was evidenced in 74 (21%) patients (50 patients with a single TP53 mutation and 24 patients with more than one). All these cases would have been missed by conventional sequencing. Among the 343 patients, 113 (33%) were poly-mutated and harbored more than one pathogenic TP53 variants (2 to 11 variants per patient): 57 (16,7 %) had 2 variants, 32 (9,3%) had 3, 10 had 4 (3%) and 14 patients (4%) had 5 to 11 variants. Using both long range sequencing and in silico analysis, we could show that all these variants were distributed in different alleles supporting an important intratumoral heterogeneity and a strong selection for TP53 loss of function during tumor progression in these patients. Null variants were rarely found as single alteration: only 46 patients (13,4%) patients harbored a single null mutation. Null mutations were predominantly found in patients with multiclonal mutations (87% with 4 or more). Median size of variants significantly decreased with the number of mutations and most of low VAF (less than 10%) variants were found in multiclonal combinations. Multiclonal mutations were predominantly found in previously treated patients (41% treated versus 10 % untreated) but whether all these variants preceded treatment and were further selected is currently unknown. We observed that 71,5 % of patients were IGHV unmutated and multiclonal mutations were surprisingly more frequent in mutated IGHV cases than in unmutated ones. Only 50% of cases carried a 17p deletion, highlighting again the importance of testing for TP53 mutations in addition to FISH analysis. Presence or absence of 17p deletion was unrelated to the number of TP53 mutations. Taken together these observations suggest that the TP53 mutational landscape in CLL is very complex and can involve multiple mechanisms, converging to a total loss of TP53 function and tumor progression. NGS provides a powerful tool for detecting all these alterations including variants with low VAF and should become a standard for CLL screening prior to each line of treatment. Disclosures Leblond: Amgen: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Letestu:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Cymbalista:Abbvie: Honoraria; Roche: Research Funding; Sunesis: Research Funding; Gilead: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

Disruption of TP53 function by Point Mutations and Deletions Is Associated with An Increased Risk of Disease Progression within Previously Treated, Relapsed Chronic Lymphocytic Leukemia Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2445-2445
Author(s):  
Annika Dufour ◽  
Stefan K Bohlander ◽  
Evelyn Zellmeier ◽  
Gudrun Mellert ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Disease Progression ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Dominant Negative ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage ◽  
Previously Treated

Abstract Abstract 2445 Chronic lymphocytic leukemia (CLL) patients with a deletion of the TP53 tumor supressor gene located at 17p13 have a poor prognosis in first line chemotherapy regimens. Recent studies indicated somatic TP53 mutations as a prognostic factor in CLL independent of 17p13 deletion status. We aimed to further characterize the prognostic value and the impact of TP53 mutations on progression-free survival (PFS) in the presence and absence of a 17p13 deletion in previously treated and relapsed CLL patients within an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). We analyzed 457 patients at diagnosis for mutations in the TP53 gene using a combination of a microarray-based resequencing assay (AmpliChip p53 Test, Roche Molecular Systems, USA.) and Sanger sequencing of TP53 exons 2–10. The data were correlated with clinical and biologic markers as well as with interphase fluorescence in situ hybridization (FISH) and with PFS. Association of the clinical data with PFS was assessed by Cox proportional hazard models. To estimate the functional significance of the individual TP53 mutations we used the IARC TP53 database. TP53 mutations (n=60) were detected in 52 of 457 patients (11.4%) and included 42 missense, 4 nonsense, 8 frameshift mutations, 2 in-frame deletions and 4 mutations in splice sites. Among other clinical variables, only 17p13 deletion was associated with TP53 mutations: 27 of 52 TP53 mutated patients had a 17p13 deletion (concordance rate: 52%, Fisher's test p<0.001). Median PFS for patients with TP53 mutations (n=52, 13 months, HR=1.9 (1.4–2.7), p<0.001) was significantly shorter as compared to patients without TP53 mutations (n=480, 27 months). In a sub-group analysis, chemoimmunotherapy including Rituximab did not significantly improve the PFS of patients with TP53 mutations. Multivariate analysis including treatment arm, Binet stage, age, IGVH mutational status, 17p13 deletion and TP53 mutation status confirmed TP53 mutation status (HR-TP53=1.7 (1.1–2.6), p=0.009) as a prognostic factor for PFS independent of 17p13 deletion status (HR-17p=1.7 (1.1–2.7), p=0.024) and with a similar effect size. The other independent prognostic factors were treatment (HR=0.61 (0.48–0.76), p<0.001), Binet stage (HR=1.64 (1.3–2.1), p<0.001) and IGVH mutational status (HR=2.4 (1.85–3.1), p<0.001). To further dissect the contribution of TP53 mutation and 17p13 deletion on PFS, we considered a multivariate analysis comparing patients with both TP53 mutation and 17p13 deletion (n=28), with only 17p13 deletion (n=9), with a dominant negative TP53 mutation or multiple TP53 mutations (n=8) or with a single TP53 mutation (n=16) against patients without TP53 abnormalities (n=271), adjusted for treatment, Binet stage, age and IGVH mutational status. Patients with a predicted biallelic disruption of TP53 either by a TP53 mutation in combination with a 17p13 deletion (HR: 2.8 (1.8,4.2), p=<0.001) or patients with a dominant negative TP53 mutation as predicted by the IARC TP53 database or multiple TP53 mutations (HR=3.26 (1.5,7.1), p=0.003) had a risk similar in size and which was quite high for disease progression (the reference to calculate the risk, here and in the following, is always the group of patients without TP53 abnormalities). The risk slightly decreased for patients with only a deletion 17p13 (HR=2.2, (1.1–4.3), p=0.021). Very interestingly, single TP53 mutations showed a much lower risk for disease progression (in this case not even significant) (HR=1.61 (0.9–2.8), p=0.084) especially compared to the risk conferred by a biallelic disruption. In this large cohort of previously treated CLL patients, complete disruption of TP53 function (by a combination of a 17p13 deletion and a TP53 mutation, through dominant negative TP53 mutations or through multiple TP53 mutations) was associated with a higher risk for disease progression. Prognosis of patients with a single TP53 mutation was not significantly different from patients without TP53 aberrations. It remains to be shown whether CLL patients with a single TP53 mutation are at a higher risk of acquiring additional mutations of TP53 during disease progression. Prognostic stratification of previously treated CLL patients should include a routine molecular TP53 mutational analysis in addition to deletion analysis of the TP53 locus by FISH. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Mundipharma:; Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.

Prognostic Significance Of TP53 mutations and Single Nucleotide Polymorphisms In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4971-4971
Author(s):  
Simon B. Zeichner ◽  
Sarah Alghamdi ◽  
Gina Elhammady ◽  
Robert Poppiti ◽  
Amilcar Castellano-Sanchez
Keyword(s):  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Performance Status ◽  
Nucleotide Polymorphisms ◽  
Complex Karyotype ◽  
Single Nucleotide ◽  
Tp53 Mutations ◽  
Significant Difference ◽  
De Novo Aml

Abstract Background The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median OS ranging from several months to more than 10 years. Age at diagnosis, performance status (PS), and karyotype expression have long been established in prognostication. Loss of TP53, a tumor suppressor gene located on the short arm of chromosome 17, is one of the most frequent genetic abnormalities in human cancer and is one of the more promising prognostic markers for AML. Studies have shown that TP53 mutations are present in 5-25% of all AML patients, in 70% of those with complex karyotypes, and are associated with old age, chemotherapy resistance, and worse OS. Single nucleotide polymorphisms (SNPs), changes in DNA seen in an appreciable amount of the population, have been examined in AML and studies have suggested a possible correlation with worse outcomes. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized TP53 mutations and SNPs would mimic the literature, occurring in a minority of patients, and conferring a worse OS. Methods We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n =10). Immunohistochemical (IHC) analysis of bone marrows and peripheral blood smears was assessed via DO-1 antibody on paraffin embedded tissue. Conventional cytogenetic analyses were performed on short-term cultured bone marrow and peripheral blood cells with the use of the GTG-banding technique. TP53 PCR sequencing was performed using DNA from bone marrow smears using the Sanger sequencing platform and resolved by capillary electrophoresis. Analysis was performed using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Descriptive frequencies and median survivals were calculated for demographic information, prognostic factors, and treatment variables. A univariate analysis was performed. Results The majority of patients in our pilot study were older than age 60 (80%), male (60%), Hispanic (60%), and had a poor PS (ECOG 2-3: 60%). Most patients had de-novo AML (50%) with an intermediate (50%) non-complex (70%) karyotype and a TP53 P72R SNP (50%). Fewer than half of these patients harbored TP53 mutations (40%). There was no significant difference in OS based on sex, AML history, risk-stratified karyotype, or TP53 mutation. There was a trend toward improved survival among patients younger than age 60 (11, 4 mo, p = 0.09), of Hispanic ethnicity (8, 1 mo, p = 0.11), and those not harboring P72R (8, 2, p = 0.10). There was a significant improvement in survival among patients with a better PS (28, 4 mo, p = 0.01) and those who did not have a complex karyotype (8, 1 mo, p = 0.03). Among patients with a TP53-mutation, there were a larger number of individuals who were younger than age 60 (25.0, 16.7%), who were male (75.0, 50.0%), had a good performance status (ECOG 0-1: 50.0, 16.7%), had de-novo AML (50.0, 66.7%), and who had an adverse karyotype (50.0, 33%). Patients with a P72R SNP were more often male (80, 40%) and had a worse PS (ECOG 2-3: 80, 40%) with AML secondary to MDS (60, 20%) and a complex karyotype (40, 0%). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Patients with more than one TP53 mutation had a worse clinical course than those with only a single mutation. Conclusion Our study demonstrated that poor PS and the presence of a complex karyotype were associated with a decreased OS. TP53 mutations were relatively uncommon, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a trend toward worse OS among patients with a specific SNP. These results suggest that different TP53 mutations and SNPs should not be treated the same, and that some may confer a worse prognosis than others. Larger studies are needed to validate these findings. Disclosures: No relevant conflicts of interest to declare.

Bortezomib Plus Melphalan and Prednisone (VMP) Followed By Lenalidomide and Dexamethasone (Rd) in Newly Diagnosed Elderly Myeloma Patients Overcome the Poor Prognosis of High-Risk Cytogenetic Abnormalities (CA) Detected By Fluorescence in Situ Hibridization (FISH)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4243-4243 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Norma C Gutierrez ◽  
María-Luisa Martín ◽  
Joaquín Martínez-López ◽  
Miguel T Hernandez ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Risk Group ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
The Poor ◽  
Risk Patients ◽  
Standard Risk

Abstract Background: Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. Bortezomib-based combinations have shown to improve the outcome of patients with high-risk CA but they do not completely overcome their adverse prognosis. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). There weren't differences in the rates of CA according to the treatment arm. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 37 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 36 months, p=0.01, HR 2.2, 95% IC 1.1-4.2) and this also translated into a significantly shorter 4-years OS (27% vs 72%, p=0.006, HR 3.3, 95% IC 1.4-7.7). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (32 months vs 30 months) and 4-years OS (64% vs 60%). This effect was observed only in the sequential arm applied to either t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (33 months vs 30 months) and 4-years OS (58% vs 65%) in the whole series and no differences were observed in the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy. Gironella:Celgene Corporation: Consultancy, Honoraria. Paiva:BD Bioscience: Consultancy; Binding Site: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Puig:Janssen: Consultancy; The Binding Site: Consultancy. San Miguel:Millennium: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria.

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