Relative Impact of NOTCH1/SF3B1 Mutations, Complex Karyotype and TP53 Disruption in the Prognosis of Chronic Lymphocytic Leukemia Patients.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2879-2879
Author(s):  
Loic Ysebaert ◽  
Stephanie Struski ◽  
Nais Prade ◽  
Romain Guieze ◽  
Guy Laurent ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Impact ◽  
Relative Role ◽  
Complex Karyotype ◽  
First Line ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Binet Stage ◽  
Notch1 Mutations

Abstract Abstract 2879 Introduction: Whole genome and exome sequencing studies recently revealed that CLL genome harbors frequent recurrent mutations as NOTCH1, TP53 and SF3B1 genes. Mutational status of these three genes strongly impacted on treatment-free survival (TFS) and overall survival (OS) in pioneer reports. In this retrospective series, we evaluated the relative role of these mutations along with the karyotype in untreated CLL patients, and after immunochemotherapy given first-line. Patients and methods: 164 patients were included (all naïve from chemotherapy), including 108 who further necessitated therapy according to NCI2008 guidelines. Mutational studies (IgVH sequence, NOTCH1, SF3B1, and TP53 genes) were available in 164/164, FISH (del17p and 11q) in 156/164, and conventional karyotype in 140/164. TFS and OS were calculated from diagnosis and first-line treatment or death respectively, progression-free survival (PFS) was calculated in 108 patients who received rituximab-based immunochemotherapy frontline (94 FCR, 14 R-alkylators), from end of therapy to relapse (according to NCI2008 definition). In 60/94 patients, minimal residual disease (MRD) was assessed three months after completion of FCR by 4-color flow cytometry, according to published guidelines for MRD monitoring. Results: Thirty-seven patients (22.6%) have at least one somatic mutation (TP53, SF3B1 or NOTCH1 genes), 22 NOTCH1 mutations (13.4%), 10 SF3B1 mutations (6.1%) and 8 TP53 mutations (4.5%). SF3B1 mutations are located mainly on the exon 14. TP53 mutations are located mainly on the exon 8 (4/9) and double mutation of TP53 was not detected. Three patients had a mutation of NOTCH1 or SF3B1 combined to a TP53 mutation. Conventional karyotype was obtained in 135/140 CLL (96.4%, 5 culture failures) and 116/135 (85.9%) were associated with chromosomal aberrations. Complex karyotype (CK) and balanced translocations involving IgH locus were shown in 23.9% and 8.1% of patients, respectively. NOTCH1 mutations were found significantly associated with unmutated IgVH and trisomy 12, SF3B1 mutations with male gender and advanced Binet stage, both somatic mutations being mutually exclusive. As expected, TP53 mutations associated with del17p. After a median follow-up of 5 years, 108/164 patients had received frontline immunochemotherapy, for a median treatment-free survival (TFS) of 41.6 months from diagnosis of CLL. Only 8/164 had died, for a median overall survival (OS) not reached, but a 10y probability of survival of 92%. On univariate analysis, shorter TFS was correlated with age<65y, del11q, mutation of SF3B1, CK, IgVH unmutated, and Binet stage (B versus A), only the two latter remaining significant on multivariate analysis. Shorter OS was correlated to male sex, mutation of SF3B1, CK, and dysfunctional TP53 pathway (by mutation and/or deletion), only the three latter remaining significant on multivariate analysis. A total of 108 patients received immunochemotherapy first-line (FCR in 94 patients, and rituximab-alkylating agent in 14 patients (R-CHOP, R-CVP, R-CD, R-bendamustine). Frequencies of NOTCH1 and SF3B1 mutations, and of CK were 17.7%, 8% and 32.2% respectively. On multivariate analysis, variables associated with PFS (older age, TP53 disruption, and MRD level 3 months after completion of FCR), time-to-next-treatment and OS (CK and TP53 disruption) further demonstrated that TP53 deletion/mutation and conventional karyotyping should be prospectively assessed before initiation of FCR. Of note, our data also suggested that FCR could have overcome the previously reported prognostic impact of NOTCH1 and SF3B1 mutations. Conclusions: Despite similar frequencies and distributions among defined prognostic groups (Binet, IgVH, FISH), NOTCH1 mutations were not associated with reduced TFS or OS in CLL patients naive from treatment, whereas SF3B1 mutations correlated with OS. In the 108 patients receiving immunochemotherapy, TP53 disruption and complex karyotype were independently and significantly linked to OS. This study is the first to suggest that FCR therapy may overcome the reported adverse prognosis endowed with NOTCH1 mutations. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Molecular Mutations in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) on Allogeneic Hematopoietic Cell Transplant (HCT) Outcomes: Adverse Impact of TET2 Mutations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 740-740 ◽  
Author(s):  
Betty K. Hamilton ◽  
Navneet S. Majhail ◽  
Cassandra M Hirsch ◽  
Bartlomiej Przychodzen ◽  
Lisa A. Rybicki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Complex Karyotype ◽  
Monosomy 7 ◽  
Mutation Status ◽  
Tp53 Mutations ◽  
Allogeneic Hct ◽  
Molecular Abnormalities ◽  
Tet2 Mutation

Abstract AML and MDS are heterogeneous myeloid neoplasms with variable biologic and clinical outcomes. Although allogeneic HCT is the only potentially curative therapy for high risk AML and MDS, survival after transplant remains poor, and identifying who benefits is challenging. We hypothesized that next-generation sequencing (NGS) mutational analyses can predict outcome in MDS and AML patients undergoing allogeneic HCT. We performed multi-amplicon targeted pre-HCT NGS using a somatic panel of the 60 most commonly mutated genes in myeloid neoplasias as previously determined by whole exome sequencing, on 123 patients with AML (N=64, 52%) and MDS (N=59, 48%) who subsequently underwent HCT. Median age at transplant was 53 years (range, 20-73). 21 (17%) patients had complex karyotype, 10 (8%) with monosomy 7, 48 (39%) normal, and 48 (39%) with other or unknown cytogenetic abnormalities. 45 (37%) patients were in a complete remission (CR) prior to transplant, while 78 (63%) were in less than a CR; with CR as defined by International Working Group criteria for MDS, or <5% blasts for AML. The majority of patients received myeloablative conditioning (N=83, 68%), and 40 (33%) received a reduced-intensity preparative regimen. Donor source was matched sibling (N=52, 42%), matched unrelated (N=56, 46%), cord-blood (N=12, 10%), and haplo-identical (N=3, 2%). Median follow up was 35 months (range 5-178). Mutations were analyzed individually and by molecular pathway. 88 (72%) patients had at least one mutation, most frequently in STAG2 (10.2%), TET2 (9.8%), ASXL1 (8.1%), and RUNX1 (8.1%). TP53 mutations were more common in MDS patients compared to AML (10% versus 1.6%, P=0.05). NRAS (P=0.019) and TP53 (P=0.022)mutations were more commonly associated with complex karyotype. Mutations in BCOR (P=0.048) and TP53 (P=0.047)were associated with less than CR, while TET2 (P=0.03)mutations were associated with CR prior to HCT. In univariable analyses, the presence of complex karyotype was associated with shorter overall (OS) and relapse-free survival (RFS) (hazard ratio [HR] 2.4; P=0.002 and HR 3.1; P<0.001). Mutations in TET2 (HR 2.1; P=0.042) and EZH2 (HR 2.3; P=0.048), or presence of any mutation in the histone modification pathway (ASXL1, EZH2, KDM6A, SUZ12); (HR 1.7; P=0.039) was associated with poor OS. The presence of any mutation in the DEAD box RNA-helicase family genes (DHX29, DDX54, DDX41) was associated with poor RFS (HR 3.1; P=0.009). Nothing except complex karyotype was specifically associated with higher relapse. Unlike in previous reports, TP53 mutations were not found to be significantly associated with poor OS or RFS, though these cases (N=7) were limited. In multivariable analyses, adjusting for clinical variables, complex karyotype remained significantly associated with poor OS (HR 2.7; P<0.001) and RFS (HR 3.9; P<0.001). TET2 also remained independently associated with poor OS (HR 2.4; P=0.022). Presence of any of the DNA methylation mutations (TET2, DNMT3A, IDH1, IDH2) was associated with poor RFS (HR 1.7; P=0.05). 3-year OS was 23% in patients with a complex karyotype versus 48% in patients without (P=0.002); and 14% in patients with a TET2 mutation and 46% without (P=0.042) (Figure 1). Molecular abnormalities are important variables in determining outcome after allogeneic HCT. We demonstrate that TET2 mutations in AML and MDS predict for poor survival after HCT. Ongoing serial mutational analyses in an extended cohort of patients will enhance our understanding of the role of NGS in informing care decisions for patients undergoing allogeneic HCT for AML and MDS. Figure 1. Overall Survival by TET2 mutation status Figure 1. Overall Survival by TET2 mutation status Disclosures Majhail: Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

CD49d Prevails over the Novel Recurrent Mutations As Independent Prognosticator of Overall Survival in Chronic Lymphocytic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1706-1706
Author(s):  
Michele Dal Bo ◽  
Pietro Bulian ◽  
Riccardo Bomben ◽  
Antonella Zucchetto ◽  
Francesca Rossi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
The Novel ◽  
Analysis Model ◽  
Mutational Status ◽  
Notch1 Mutations

Abstract Background. CD49d, the alpha-chain of the integrin heterodimer VLA-4, has been identified among the strongest predictors of overall survival (OS) in chronic lymphocytic leukemia (CLL), along with IGHV mutational status and deletion of the 17p (17p-) chromosome involving TP53 (Bulian et al, JCO, 2014). In addition to TP53, the clinical relevance of NOTCH1, SF3B1 and BIRC3 gene mutations has been recently emphasized. Aim. To test the relevance of CD49d in molecular subgroups of CLL defined by NOTCH1, SF3B1 and BIRC3 gene mutations. Methods. The study was based on a cohort of 778 unselected CLL (422 untreated and 356 treated cases) all characterized for CD49d expression (CD49dhigh, ≥30% positive cells by flow cytometry in 229 cases), IGHV mutational status (unmutated, UM, in 262 cases), karyotype abnormalities according to the hierarchical stratification (13q- in 308 cases, +12 in 103 cases, 11q- in 64 cases), tested at diagnosis, along with mutations/deletions (hereinafter, disruption) of TP53 (disrupted in 84 cases, including 58 cases with 17p-), BIRC3 (disrupted in 59 cases), and mutationsof NOTCH1 (mutated in 81 cases), SF3B1 (mutated in 54 cases)tested at diagnosis in 65% of cases, in all cases before therapy. Chromosome abnormalities by FISH were defined by using a 5% cut-off; IGHV, TP53, BIRC3, NOTCH1 and SF3B1 mutations were investigated by Sanger sequencing. Median follow-up of patients was 80 months with 173 deaths. Results. i) association with CD49d: a CD49dhigh phenotype associated with age ≥65 years (p=0.0001), Rai stage I or higher (p>0.0001), UM IGHV status (p>0.0001), absence of 13q- (p=0.0001), presence of +12 (p<0.0001), presence of NOTCH1 mutations (p<0.0001). ii) CD49d prognostic impact: in univariate analysis, the following covariates had a significant impact on OS: age ≥65 years (hazard ratio/confidence interval (HR/CI)= 3.98/2.77-5.73; p<0.0001), Rai stage I or higher (HR/CI=1.81/1.33-2.46; p=0.0002), high CD49d expression (HR/CI=2.62/1.94-3.54; p<0.0001), UM IGHV status (HR/CI=3.03/2.24-4.10; p<0.0001), presence of 13q- (HR/CI=0.52/0.37-0.71; p=0.0001), +12 (HR/CI=1.59/1.08-2.33; p=0.0183), 11q- (HR/CI=2.16/1.42-3.30; p=0.0004), NOTCH1 mutations (HR/CI=2.66/1.82-3.88; p<0.0001), SF3B1 mutations (HR/CI=1.99/1.24-3.20; p=0.0048), BIRC3 disruption (HR/CI=2.41/1.58-3.68; p<0.0001), TP53 disruption (HR/CI=3.23/2.28-4.57; p<0.0001). In a multivariate analysis model including all these variables, high CD49d expression (HR/CI=1.76/1.28-2.42; p=0.0006), UM IGHV status (HR/CI=2.21/1.58-3.09; p<0.0001), presence of 11q- (HR/CI=2.11/1.35-3.31; p=0.0011), TP53 disruption (HR/CI=2.93/2.04-4.22; p<0.0001), and NOTCH1 mutations (HR/CI=1.76/1.16-2.67; p=0.0082) emerged as independent prognosticators, along with age ≥65 years (HR/CI=3.73/2.58-5.39; p<0.0001). iii) CD49d prognostic impact using the integrated hierarchical mutational/cytogenetic model: by integrating gene mutations and cytogenetic aberrations according to Rossi et al (Blood, 2013), a multivariate analysis model was applied with the following covariates: age, CD49d, IGHV status, TP53/BIRC3 disruption, NOTCH1 mutations/SF3B1 mutations/11q-, normal karyotype/+12, 13q-. Again, CD49dhigh phenotype (HR/CI=1.88/1.38-2.54; p=0.0001), UM IGHV status (HR/CI=2.16/1.54-3.01; p<0.0001), presence of NOTCH1 mutations/SF3B1 mutations/11q- (HR/CI=1.62/1.11-2.38; p=0.0139), and of TP53/BIRC3 disruption (HR/CI=2.67/1.92-3.70; p<0.0001) retained their independent prognostic impact, along with age ≥65 years (HR/CI=3.58/2.28-5.17; p<0.0001). Notably, CD49dhigh CLL patients experienced shorter OS than the CD49dlow cases in the context of each mutational/cytogenetic group (TP53/BIRC3 disruption, p=0.0064; NOTCH1 mutations/SF3B1 mutations/11q-, p=0.05; normal karyotype/+12, p=0.0153; 13q-, p=0.0126; see Figure). Conclusion. CD49d was confirmed as independent negative OS prognosticator in CLL also when the novel recurrent alterations of NOTCH1, BIRC3, and SF3B1 genes were considered. In this setting, TP53 disruption and NOTCH1 mutations remained independent OS prognosticators, allegedly for their physiopathological roles in CLL cell immuno-chemoresistance. Figure 1. Figure 1. Disclosures Gaidano: Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding.

Analysis of Kohne's prognostic index in KRAS wild-type patients with metastatic colorectal cancer (mCRC) treated with salvage-line cetuximab-based regimen: HGCSG0901.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 634-634
Author(s):  
Ayako Doi ◽  
Satoshi Yuki ◽  
Yasushi Tsuji ◽  
Takahide Sasaki ◽  
Hiraku Fukushima ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Prognostic Impact ◽  
Wild Type ◽  
Free Survival ◽  
Significant Difference

634 Background: In the treatment for mCRC, it is essential for understanding the prognosis of each individual patient. Köhne’s index (KI) based on performance status, white blood cell count, alkaline phosphatase and number of metastatic sites has been previously proposed. However, in the salvage setting, the validity of KI has not been reported in patients treated by cetuximab-based chemotherapy. Methods: 269 patients with mCRC treated by cetuximab contained chemotherapy were retrospectively registered from 27 centers in Japan. This analysis was included in the KRAS wild-type patients who were refractory to or intolerant for 5-FU/irinotecan/oxaliplatin and were never administered anti-EGFR-antibody. Univariate and multivariate analysis for overall survival were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. The analysis was also designed to determine whether the Köhne’s classification could be extended to other endpoints such as progression-free survival. Results: All data were available for prognostic categorization in 127 patients. Median overall and progression-free survival was 9.8 and 4.2 months. The distribution and median survival / progression-free survival for KI were as follows: low risk (L) (n = 40; 13.1/5.1 months), intermediate risk (I) (n = 17; 9.6/3.5 months), and high risk (H) (n = 70; 7.6/4.1 months). For overall survival, there was significant difference between L and H (p = 0.004), but not between L and I (p = 0.213), and between I and H (p = 0.321). For progression-free survival, there was tended to difference between L and H (p = 0.083), but not between L and I (p = 0.392), and between I and H (p = 0.630). In Cox multivariate analysis, KI showed an independent prognostic impact (HR 1.370, p = 0.010), but not predictive impact (HR 1.147, p = 0.212). Conclusions: In this analysis, KI might be a prognostic factor in salvage treatment with cetuximab-based regimen, but no effect predicted impact. Moreover, the prospective evaluation is needed for the further validation.

scholarly journals In Chronic Lymphocytic Leukemia the Gain of the Short Arm of Chromosome 2 Is Highly Associated with an Unmutated IGHV status, 11q/ATM Deletion, SF3B1 Mutation and a Complex Karyotype

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4379-4379
Author(s):  
Claudia Haferlach ◽  
Sabine Jeromin ◽  
Anna Stengel ◽  
Manja Meggendorfer ◽  
Melanie Zenger ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cox Regression ◽  
Prognostic Impact ◽  
Chromosome 2 ◽  
Complex Karyotype ◽  
Employment Equity ◽  
Cox Regression Analysis ◽  
Tp53 Mutations ◽  
Equity Ownership

Abstract Background: CLL is characterized by a distinct pattern of translocations, genomic gains and losses and molecular mutations. The most frequent abnormalities such as trisomy 12 and deletions of 6q, 11q, 13q and 17p have been intensively studied. However, data on less frequent recurrent abnormalities such as the partial gain of the short arm of chromosome 2 is lacking. Aims: a) Determine the frequency of 2p gain in CLL, b) Characterize the size and the commonly gained region, c) Analyze the spectrum of additional cytogenetic abnormalities and molecular mutations, and d) Evaluate the prognostic impact. Patients and Methods: Chromosome banding analysis (CBA) revealed a gain of 2p in 113 out of 5564 (2%) CLL cases. In 72 cases with sufficient material genomic array analysis (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany) and determination of the mutation status of TP53, SF3B1 and IGHV were performed. Results:76% of patients with gain of 2p were male. The median WBC count was 33,700/µL (range: 5,900 - 228,000). Median age was 66 years (range: 29 - 87). The gain of 2p always encompassed the 2p telomere (2pter) while the centromeric border of the 2p gain varied between 2p21 and the centromere of chromosome 2 (2p10) (genomic positions 45,859,076 to 92,297,003). The gain of 2p was the sole chromosomal abnormality in only 8/72 cases (11%) and was accompanied by one, two or more than two additional aberrations in 10, 20, and 34 cases. In total 209 chromosome abnormalities were observed in addition to the 2p gain (median per patient: 2, range: 0-16). Of these only 21 were balanced while 188 were unbalanced abnormalities leading to gain or loss of chromosomal material. Gain of 2p was most frequently accompanied by deletions in 13q (total: 74%, homozygous: 11%), 11q (56%), 18p (18%), and 6q (13%) and gains of 8q (11%). 17p deletions were present in 6% of cases. In 49 cases (68%) the gain of 2p was present in the main clone while it was present in a subclone only in 23 cases (32%). The gain of 2p material was due to a duplication in the short arm of chromosome 2 in 10 cases, while a gain of an isochromosome 2p was present in 3 cases. In the remaining cases material of the short arm of chromosome 2p was attached to a variety of different partner chromosomes. The most frequent acceptor chromosome was chromosome 18 (n=13; 18%). In two cases (2%) 2 IGH rearrangements were observed of which one was mutated and the other unmutated. The IGHV status was unmutated (IGHV-U) in 66 (92%) and mutated in only 4 cases (6%). Three of these 4 cases with mutated IGHV showed only a low mutation rate (sequence homology to germline 97-97.9%). Stereotyped B-cell receptors were present in 14 cases (19%). SF3B1 mutations were observed in 21 cases (29%) with a median mutation load (ML) of 39% (range: 10-51%). TP53 mutations were detected in 8 (11%) cases (median ML: 60%, range: 13-100%). In 2 patients with a TP53 mutation a TP53 deletion was present and in 3 cases a copy neutral loss of heterozygosity (CN-LOH) of 17p was detected leading to TP53 wild-type loss in these 5 cases. TP53 mutations were less frequent in cases harboring the gain of 2p as the sole abnormality (3% vs 21%, p=0.02) The prognostic impact of 2p gain was evaluated in an unselected cohort of 1381 CLL cases with available follow up data (median follow up: 5.1 years) including 22 cases with 2p gain. The frequency of IGHV-Ustatus, SF3B1 mutations and 11q/ATM deletions was significantly higher in CLL with 2p gain compared to cases without (for all p<0.05). In univariate Cox regression analysis gain of 2p was significantly associated with shorter overall survival (OS) (relative risk (RR): 2.1; p=0.05). 5 year OS was 69% in CLL with 2p gain compared to 85% in cases without 2p gain (p=0.05). However, in multivariate analysis only IGHV-U, mutations in SF3B1 and TP53 and TP53/17p deletion were independently associated with shorter OS, while gain of 2p and 11q/ATM deletion were not. 2p gain was associated with shorter time to treatment (TTT) (RR: 2.0; p=0.02). In multivariate analysis only IGHV-U, SF3B1 mutation and 11q/ATM and TP53/17p deletion were independently associated with shorter TTT, while gain of 2p and TP53 mutations were not. Conclusions:CLL with gain of 2p is highly associated with an unmutated IGHV status (92%), a high frequency of 11q/ATM deletion (56%), 13q deletion (74%), SF3B1 mutation (29%) and a complex karyotype (47%). Data suggest that gain of 2p is a later event in CLL pathogenesis and might be a marker of progression. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Jeromin:MLL Munich Leukemia Laboratory: Employment. Stengel:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Zenger:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

scholarly journals P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii32-iii32
Author(s):  
H Noor ◽  
R Rapkins ◽  
K McDonald
Keyword(s):  
Overall Survival ◽  
Tp53 Mutation ◽  
Progression Free Survival ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Wild Type ◽  
Mutation Status ◽  
Free Survival ◽  
Tp53 Mutations ◽  
Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

AN INDIAN PROSPECTIVE STUDY OF DOCETAXEL THERAPY IN CRPC: CAN PRETREATMENT FACTORS PREDICT THE RESPONSE

2021 ◽  
pp. 78-81
Author(s):  
Devashish Kaushal ◽  
Rajeev Sood
Keyword(s):  
Overall Survival ◽  
Alkaline Phosphatase ◽  
Multivariate Analysis ◽  
Gleason Score ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Poor Overall Survival ◽  
Free Survival ◽  
Carcinoma Prostate

Introduction: Studies on the effects of chemotherapy in Indian Castration-Resistant Prostate Cancer (CRPC) patients are very limited and world data is inconsistent. The purpose of the present study is to assess the effects of Docetaxel therapy in CRPC in Indian patients in terms of survival benet, both progression-free survival, and overall survival. This study also analyzes the effects of various factors on the survival of CRPC patients. Methodology: This is a single institutional prospective observational study. CRPC patients were treated with Docetaxel and followed till death as the primary endpoint or till the end of the study. Survivals were calculated with the Kaplan Meier method. Factors affecting survival were analyzed with univariate and multivariate analysis by log-rank t-test and Cox proportion hazard regression analysis. Result: Out of enrolled 101 patients, 78 were treated with Docetaxel. A decline in PSA (>50% reduction) was observed in 61.54%. Radiological response of regression noted in 40 % Nuclear Bone Scan and 19.23% CT/MRI by RECIST criteria. Progression-free survival and overall survival with Docetaxel (n=78) were 11.8 and 21 months respectively. Hemoglobin less than 11 gm%, Alkaline phosphatase more than 115 IU/dl, PSAmore than 14 ng/ml, Gleason score more than 7 and duration from diagnosis of carcinoma prostate to CRPC less than 24 months, the number of chemotherapy cycles less than 6 were all found to be signicantly associated with poor overall survival in univariate analysis while only Hemoglobin (P=0.0159) showed an independent association with overall survival in multivariate analysis. Conclusion: Overall and progression-free survival of CRPC patients with Docetaxel is 21 & 11.8 months respectively. Hemoglobin, Alkaline phosphatase, PSA, Gleason score, Docetaxel cycle, and duration from diagnosis of carcinoma prostate to CRPC were found to be signicantly associated with poor overall survival.

Efficacy and prognostic significance of triflurodine/tipiracil beyond oxaliplatin and irinotecan based chemotherapy in patients with refractory metastatic colorectal cancer: An observational multicenter study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15586-e15586
Author(s):  
Mohamed Alghamdi ◽  
Shouki Bazarbashi ◽  
Elsamany Shereef ◽  
Mervat Mahrous ◽  
Omar Al shaer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Saudi Arabia ◽  
Neutrophil Count ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
P Value ◽  
Second Line ◽  
First Line ◽  
Free Survival

e15586 Background: In Saudi Arabia, the incidence of colorectal cancer has been increased over the past few years. The optimal treatment beyond the second line is not fully understood. To the best of our knowledge, the efficacy and disease outcomes of triflurodine/tipiracil in Saudi patients with refractory metastatic colorectal cancer(mCRC) has not been studied yet. Our study is a real-life practice evaluation of the efficacy of triflurodine/tipiracil in patients with refractory mCRC. Moreover, the prognosis and the prognostic significance of the different clinical variables have been analyzed. Methods: A retrospective, multi-centers ( 5 centers representative of Saudi Arabia )observational study in patients with mCRC who have received triflurodine/tipiracil beyond oxaliplatin & Irinotecan-based chemotherapy between December 2018-December 2020.We aimed to assess the response to triflurodine/tipiracil, to evaluate the progression-free survival (PFS ), the overall survival (OS), and the associated factors of prognostic significance. Results:The data of 100 patients with refractory mCRC who has received triflurodine/tipiracil have been analyzed. The mean age was 55.2 +11.8 years. Forty-two patients were (42%) females and 58 (58%) were male patients. Sigmoid was the most common primary site of cancer in 35 (35%) patients, followed by rectum 29 (29%). Peritoneal metastasis was present in 17 (23.3%) patients ,liver in 51(56.6%) and lung in 39 (50.7%). Metastatic sites were ≥ 2 in 45 (45%) patients. Metastatic lesions were ≥ 5 in 65 (65%) patients. Xelox chemotherapy regimen was the most commonly used first-line chemotherapy which represents 43%, while Folfiri or Xeliri combination was the most used second line in 57 (60%). For the third line, Folfox or Xelox was used in 81 (83.5%) patients. The fourth line was given to 49 (67.1%). For first-line biological agents, Cetuximab was used most frequently 31 (46.3%).Evaluation of the response to treatment with triflurodine/tipiracil revealed one patient (1%) with a complete response,3 patients (3%) with partial response, 28 (28%) patients with stable disease, and 66 (66%) showed progressive disease. The estimated median progression-free survival was 5 months ( 3.839 - 6.161) and the median overall survival was 12 months (9.732-14.268). The log-rank analysis showed that the baseline neutrophils ≤ 75 % ( P-value= 0.0092) and low hemoglobin level (P-value= 0.0245) were strongly associated with a higher survival. By multivariate Cox regression analysis, the neutrophil count ≤ 75 % was the only independent predictor for survival. Conclusions: Trifluridine/tipiracil is effective in patients with refractory mCRC. The low neutrophil count might predict a better overall survival.

Prognostic and predictive factors in early stages of classic Hodgkin’s lymphoma

2022 ◽  
pp. 7-15
Author(s):  
T. I. Bogatyreva ◽  
A. O. Afanasov ◽  
A. Yu. Terekhova ◽  
N. A. Falaleeva
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Hodgkin’S Lymphoma ◽  
Early Stage ◽  
Hodgkin's Lymphoma ◽  
Cure Rate ◽  
First Line ◽  
Bulky Disease ◽  
Cox Regression Analysis ◽  
Early Stages

Rationale. In the early stages of classical Hodgkin’s lymphoma (cHL), the cure rate reaches 85–95 %, but the long-term effects of therapy can worsen overall survival. Current trials for early stages of Hodgkin’s lymphoma with favorable prognosis address the task of maintaining cure rates while reducing sequelae. For early unfavorable stages, the challenge is to improve cure rate without increasing toxicity.Purpose. To assess the potential significance of individual risk factors for optimal choice of the first line chemotherapy in early-stage Hodgkin lymphoma.Materials and methods. This single-center retrospective study included 290 patients with early stage cHL who had received ABVD – based (n = 249; 86 %) or BEACOPP‑21 – based (n = 41; 14 %) combined modality therapy from 2000 to 2017. Progression-free survival (PFS) and overall survival (OS) were assessed in Cox regression analysis including 12 clinical parameters.Main results. At a median follow up of 60 months for the entire group, OS was 95 % and PFS was 89 %. In a multivariate analysis PFS, at 5 years, was significantly inferior in patients with mediastinal bulk, baseline lymphocytopenia (≤ 0.6 × 109/L, р = 0.002; < 1.0 × 109/L, р = 0.000) and male gender; OS was inferior only in patients with an absolute lymphocytopenia (AL). In patients with AL, PFS after ABVD-based regimen was, respectively, 12 % in the high-risk group with mediastinal bulk and 56 % without it. PFS of patients without AL when treated with ABVD did not differ compared to BEACOPP‑21 within the same prognostic group: 95.2 % vs. 92.3 % for non-bulky and 86.4 % vs. 84.2 % for bulky disease. In the absence of AL, mediastinal bulk remained the main and only risk factor in multivariate analysis.Conclusions. The ABVD regimen is highly effective in the first line of chemotherapy for cHL, except for cases with baseline lymphocytopenia, in which the early usage of the BEACOPP regimen in the escalated or 14-day variants might be justified. In patients with mediastinal bulk, standard chemotherapy is not effective enough even in the absence of AL; therefore, if an intermediate PET/CT scan is available, it seems more appropriate to use a milder ABVD regimen on the first line and leave intensive therapy for patients with proven refractory disease. Prospects for improving the efficiency are opened with the new N-AVD and A-AVD schemes, the benefits of which should be evaluated, first of all, in patients with AL and mediastinal bulk.

Sign in / Sign up

Export Citation Format

Share Document