TP53 Mutations Detected By Next-Generation Deep-Sequencing In Patients With Myelodysplastic Syndrome and Isolated Deletion (5q): Results From a German Multicenter Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2759-2759
Author(s):  
Maximilian Mossner ◽  
Johann-Christoph Jann ◽  
Evi Lauinger-Lörsch ◽  
Daniel Nowak ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Research Funding ◽  
Mutation Frequency ◽  
Treatment Initiation ◽  
Detection Sensitivity ◽  
Oligonucleotide Primer ◽  
Next Generation ◽  
High Quality ◽  
Tp53 Mutations

Abstract Background Beside cytogenetic aberrations, additional gene mutations are powerful predictors of outcome in myeloid diseases. Moreover, myelodysplastic syndromes with isolated deletion (5q) (MDS del(5q)) have been regarded as one of the most favorable entities among MDS. However, a substantial proportion of MDS del(5q) patients experience transformation into AML soon after diagnosis (Germing et al. Leukemia. 2012;26:1286-1292). Mutations of TP53 gene have early been recognized as an unfavorable prognostic biomarker in MDS in general and recent data suggest a role of TP53 mutations in the transformation of MDS del(5q) into AML. Lenalidomid (Len) is now approved in the US as well as in Europe for the treatment of MDS del(5q) it is of particular interest whether Lenalidomide can alter the course of pretreatment TP53 mutated MDS del(5q). Methods The Le-Mon-5 trial investigated the safety and efficacy of Len in patients with MDS and isolated deletion (5q). All patients gave their written informed consent to the clinical trial and to additional molecular genetic analyses. Bone marrow aspirates were performed at screening prior treatment initiation and during follow-up every 6 months. Only freshly extracted, high-quality DNA from ficollized mononuclear cells was used for next-generation deep-sequencing analysis. For generation of PCR amplicon libraries TP53 oligonucleotide primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) research study network. Amplicon deep-sequencing of TP53 (exons 4-11) was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden. Results Central cytological, histological and cytogenetic review was performed in all patients establishing the diagnosis of MDS with isolated deletion (5q). A total of 68 patients (male: n=9) were analyzed with a median age of 71 years (range 41-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). Mean mutation frequency was 38%. Notably, we did not find mutation frequencies lower than 15%. Of 4 evaluable patients, three patients became transfusion independent within 4 months of Len treatment. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4 and 17 months on Len treatment (27% and 51%, respectively). Noteworthy, one the two patients achieved a complete cytogenetic remission despite maintaining his TP53 mutation frequency. Conclusion Using freshly extracted DNA we achieved high-quality NGS results with a high mean coverage of the relevant coding region of TP53. However, prevalence of TP53 mutations in our patient cohort was lower as compared to previously published data and we did not find low-level allele burdens as published by other groups, which might be due to the different sample sources used. Transfusion independence as well as cytogenetic remissions can be achieved in patients with TP53 mutations who are treated with Lenalidomide. Disclosures: Platzbecker: Celgene: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Götze:Celgene Corp.: Honoraria. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Hofmann:Celgene: Research Funding. Germing:Celgene: Honoraria, Research Funding. Nolte:Celgene: Honoraria, Research Funding.

scholarly journals Clinical Impact of TP53 Mutations in Patients with MDS and Isolated Deletion 5(q) Treated with Lenalidomid: Results from the German Prospective Le-Mon-5 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1920-1920
Author(s):  
Maximilian Mossner ◽  
Johann Christoph Jann ◽  
Evi Launiger-Lörsch ◽  
Daniel Nowak ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Detection Sensitivity ◽  
Next Generation ◽  
Tp53 Mutations ◽  
Transfusion Independence ◽  
Blast Count ◽  
Generation Sequencing

Abstract Introduction: MDS with isolated deletion 5(q) accounts for approximately 5% of all MDS cases. A recent retrospective analysis has found a cumulative progression rate of 18% after 5 years in patients with MDS deletion 5(q) without an increased medullary blast count[1]. Retrospective analyses have indicated that mutations in TP53 have an adverse impact on the clinical course of affected patients and their response to Len treatment. Here we report on the results of the German multi-center, prospective Le-Mon-5 trial that investigated the safety and efficacy of lenalidomide (Len) in patients with MDS and isolated deletion 5(q). Methods: Le-Mon-5 is a trial of Len in patients with MDS with isolated 5q abnormality, a blast count of < 5% in the bone marrow, a platelet count > 50.000/µl and absolute neutrophil counts of > 500/µl in the peripheral blood. Patients were treated with the standard dose of 10 mg Len for 21 days q28 days. The primary endpoint was safety. Secondary endpoints included response according to IWG criteria (2000), time to response, duration of transfusion independency and incidence and time to AML-transformation, respectively. All patients gave written informed consent to the trial including additional molecular genetic analyses. Central cytologic, cytogenetic and histologic review was performed. Mutational analysis of TP53 was done by next generation sequencing (NGS). For generation of PCR amplicon libraries TP53 primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) study network. Amplicon sequencing of TP53 was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden. Results: A total of 91 patients were enrolled into the trial. Of those, 71 patients (male, n=13) were analyzed for TP53 mutations. Median age was 71 years (range 40-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). There was no difference between the TP53 mutated (TP53mut) versus TP53 wildtype patients (TP53WT) with regard to age, IPSS risk, hemoglobin levels, absolute neutrophil counts and platelet counts at baseline. Transfusion independence was achieved in a significantly lower proportion of patients in the TP53mut group versus TP53WT group (43% vs. 62%, p=0.036). Moreover, median survival was significantly shorter in the TP53mut group as compared to TP53WT group (533 days vs. not reached, p=0.0002). No difference was seen with regard to cytologic and cytogenetic response. Data on evolution into AML are currently being collected. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4-17 months on Len treatment (27% and 51%, respectively), although one of the patients achieved a complete cytogenetic response during Len treatment. Conclusions: Using the NGS technique on a routine basis, we achieved high quality runs with a high mean coverage of analyzed exons of TP53. Presence of TP53 mutations adversely affected response to Len with regard to transfusion independence. Moreover, TP53mut patients had a shorter overall survival as compared to TP53WT patients underlining the prognostic relevance of TP53 mutations in this patient cohort. Therefore, mutation analysis of TP53 might guide treatment decisions in the future, e.g. consideration of combination regimens. Since the TP53 clone obviously prevails during Len treatment, careful monitoring for signs of transformation should be performed. Disclosures Platzbecker: Celgene Corp.: Honoraria, Research Funding. Götze:Celgene Corp, Novartis Pharma: Honoraria. Schlenk:Celgene Corp.: Research Funding, Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Germing:Celgene Corp.: Honoraria, Research Funding. Nolte:Celgene Corp., Novartis Pharma: Honoraria, Research Funding.

Simplified in-House Deep Sequencing Method of Inmunoglobulin Genes for Minimal Residual Dissease Quantification and Risk Stratification in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2972-2972
Author(s):  
Beatriz Sanchez-Vega ◽  
Santiago Barrio ◽  
Yanira Ruiz ◽  
Ramon Garcia-Sanz ◽  
Bruno Paiva ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Deep Sequencing ◽  
Research Funding ◽  
Residual Disease ◽  
Rank Test ◽  
Next Generation ◽  
Effective Technology ◽  
Patient Prognosis ◽  
Minimal Residual

Abstract BACKGROUND: The first step to the cure of Multiple myeloma (MM) is achieving a clinical complete response (CR). However, a majority of patients relapse in part due to the persistence of low levels of pathological plasma cells after treatment (minimal residual disease (MRD)). In previous work, we have shown that Next generation sequencing (NGS) of immunoglobulin (IG) rearranged genes is an effective technology to identify and quantify pathological clonal cells in MM, and also it is a good predictor of patient prognosis. However, this technology is a proprietary multiplex PCR, uses a reference plasmid, it is performed at the centralized laboratories, and it is not broadly available. AIMS: To present a new in-house simplified method for quantification of IG gene clonal rearrangements by NGS. To test the suitability of the method for MRD detection in MM patients compared with 8-color high sensitivity Flow Cytometry (8c-MFC) data on a prospective way. To determine its capability as a predictor of patient prognosis. METHOD: We use deep sequencing to prospectively analyzed DNA from bone marrow samples of 58 patients (58 diagnostic samples and 80 follow-up samples) of patients included the GEM10 clinical trial. The method employs the primers developed by BIOMED-2 for IGH and IGK, and a set of specific mathematical and bioinformatics tools. First, we identified the clonal rearrangement(s) (clonotype) in the diagnostic sample by fragment analysis and NGS. Second, we searched the NGS sequences from follow-up samples to detect and quantitate (MRD) the presence of the clonotype identified in the diagnostic sample. Overall Survival (OS) and Progression free Survival (PFS) were estimated by Kaplan-Meier survival analysis. The survival curves generated were compared with the log-rank test for trend. RESULTS: The sensitivity of the method is 10-5 for 150.000 cells. Reproducibility is >90%. The Spearman correlation coefficient between NGS and 8c-MFC data for diagnosis and follow-up samples was R=0.6903, p<0.0001. When we applied the criteria of 10-5 for NGS, discordant results were as follow: 121 cases were positive by both methods, 2 cases were positive (>10-5) by 8c-MFC but negative (<10-5) by NGS; 7 samples were negative (<10-5) by 8c-MFC but positive (>10-5) by NGS; and 7 cases were negative by both methods. Next we analyzed de correlation of OS and PFS with MRD levels determined by NGS and by 8c-MFC. For NGS data, median PFS (FigA) was 34 months for patients with values of MRD>10-5 vs not reached for patients with values of MRD<10-5 (hazard ratio [HR] = 3.69, P =0 .0109). Also, for 8c-MFC data, the patients with values of MRD<10-5 had longer PFS than those with values of MRD>10-5 (34 months versus 47; HR = 3.69, P =0 .0109). Median OS (FigB) was also significantly longer in MRD<10-5 (NGS) patients (not yet reached), compared to MRD>10-5 (NGS) patients (41 months, HR = 3.6, P =0.0495). For 8c-MFC we did not get a significant association (41 vs 50 months, HR=1.979, p=0.228). It should be noted that this comparison was made with the standard 8c-MFC and it is probable that the sensitivity will be inferior to that of the Next generation flow. There were no significant differences in terms of PFS between the data obtained by our in-house method, 8c-FCM and previous data obtained with LymphoSight technology. CONCLUSIONS: Our data confirms that analysis of MRD levels determined by deep sequencing is capable of predict survival outcomes in myeloma patients. NGS sequencing of Ig genes is an effective technology to identify and quantify pathological clonal cells in MM. This approach is a methodological and economical alternative to MFC and other methods for MRD follow-up. Figure 1. Figure 1. Disclosures Paiva: Janssen: Consultancy; Celgene: Consultancy; BD Bioscience: Consultancy; Sanofi: Consultancy; Binding Site: Consultancy; Onyx: Consultancy; Millenium: Consultancy; EngMab AG: Research Funding. Ocio:Pharmamar: Consultancy, Research Funding; MSD: Research Funding; Novartis: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Array BioPharma: Consultancy, Research Funding; Jassen: Honoraria. Mateos:Celgene: Consultancy, Honoraria; Takeda: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Onyx: Consultancy. San Miguel:Novartis: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Millennium: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria.

scholarly journals The Impact of Clonal Hematopoiesis of Indeterminate Potential on Survival in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4359-4359
Author(s):  
Koji Sasaki ◽  
Rashmi Kanagal-Shamanna ◽  
Guillermo Montalban-Bravo ◽  
Rita Assi ◽  
Kiran Naqvi ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Next Generation ◽  
Risk Of Death ◽  
Genetics Research ◽  
The Impact ◽  
Generation Sequencing

Abstract Introduction: Clearance of detected somatic mutations at complete response by next-generation sequencing is a prognostic marker for survival in patients with acute myeloid leukemia (AML). However, the impact of allelic burden and persistence of clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations on survival remains unclear. The aim of this study is to evaluate the prognostic impact of allelic burden of CHIP mutations at diagnosis, and their persistence within 6 months of therapy. Methods: From February 1, 2012 to May 26, 2016, we reviewed 562 patients with newly diagnosed AML. Next-generation sequencing was performed on the bone marrow samples to detect the presence of CHIP-associated mutations defined as DNMT3A, TET2, ASXL1, JAK2 and TP53. Overall survival (OS) was defined as time period from the diagnosis of AML to the date of last follow-up or death. Univariate (UVA) and multivariate Cox proportional hazard regression (MVA) were performed to identify prognostic factors for OS with p value cutoff of 0.020 for the selection of variables for MVA. Landmark analysis at 6 months was performed for the evaluation of the impact of clearance of CHIP, FLT3-ITD, FLT3D835, and NPM1 mutations. Results: We identified 378 patients (74%) with AML with CHIP mutations; 134 patients (26%) with AML without CHIP mutations. The overall median follow-up of 23 months (range, 0.1-49.0). The median age at diagnosis was 70 years (range, 17-92) and 66 years (range, 20-87) in CHIP AML and non-CHIP AML, respectively (p =0.001). Of 371 patients and 127 patients evaluable for cytogenetic in CHIP AML and non-CHIP AML, 124 (33%) and 25 patients (20%) had complex karyotype, respectively (p= 0.004). Of 378 patients with CHIP AML, 183 patients (48%) had TET2 mutations; 113 (30%), TP53; 110 (29%), ASXL1; 109 (29%), DNMT3A; JAK2, 46 (12%). Of 378 patients, single CHIP mutations was observed in 225 patients (60%); double, 33 (9%); triple, 28 (7%); quadruple, 1 (0%). Concurrent FLT3-ITD mutations was detected in 47 patients (13%) and 12 patients (9%) in CHIP AML and non-CHIP AML, respectively (p= 0.287); FLT3-D835, 22 (6%) and 8 (6%), respectively (p= 0.932); NPM1 mutations, 62 (17%) and 13 (10%), respectively (p= 0.057). Of 183 patients with TET2-mutated AML, the median TET2 variant allele frequency (VAF) was 42.9% (range, 2.26-95.32); of 113 with TP53-mutated AML, the median TP53 VAF, 45.9% (range, 1.15-93.74); of 109 with ASXL1-mutated AML, the median ASXL1 VAF was 34.5% (range, 1.17-58.62); of 109 with DNMT3A-mutated AML, the median DNMT3A VAF was 41.8% (range, 1.02-91.66); of 46 with JAK2-mutated AML, the median JAK2 VAF was 54.4% (range, 1.49-98.52). Overall, the median OS was 12 months and 11 months in CHIP AML and non-CHIP AML, respectively (p= 0.564); 16 months and 5 months in TET2-mutated AML and non-TET2-mutated AML, respectively (p <0.001); 4 months and 13 months in TP53-mutated and non-TP53-mutated AML, respectively (p< 0.001); 17 months and 11 months in DNMT3A-mutated and non-DNMT3A-mutated AML, respectively (p= 0.072); 16 months and 11 months in ASXL1-mutated AML and non-ASXL1-mutated AML, respectively (p= 0.067); 11 months and 12 months in JAK2-murated and non-JAK2-mutated AML, respectively (p= 0.123). The presence and number of CHIP mutations were not a prognostic factor for OS by univariate analysis (p=0.565; hazard ratio [HR], 0.929; 95% confidence interval [CI], 0.722-1.194: p= 0.408; hazard ratio, 1.058; 95% confidence interval, 0.926-1.208, respectively). MVA Cox regression identified age (p< 0.001; HR, 1.036; 95% CI, 1.024-1.048), TP53 VAF (p= 0.007; HR, 1.009; 95% CI, 1.002-1.016), NPM1 VAF (p=0.006; HR, 0.980; 95% CI, 0.967-0.994), and complex karyotype (p<0.001; HR, 1.869; 95% CI, 1.332-2.622) as independent prognostic factors for OS. Of 33 patients with CHIP AML who were evaluated for the clearance of VAF by next generation sequencing , landmark analysis at 6 months showed median OS of not reached and 20.3 months in patients with and without CHIP-mutation clearance, respectively (p=0.310). Conclusion: The VAF of TP53 and NPM1 mutations by next generation sequencing can further stratify patients with newly diagnosed AML. Approximately, each increment of TP53 and NPM1 VAF by 1% is independently associated with 1% higher risk of death, and 2% lower risk of death, respectively. The presence of CHIP mutations except TP53 does not affect outcome. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Celgene: Research Funding. DiNardo:Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Accelerated Telomere Shortening Identifies a Subgroup of Patients with Myelodysplastic Syndrome and Isolated 5q Minus Deletion with a Higher Probability of Response to Lenalidomide Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3809-3809
Author(s):  
Fabian Beier ◽  
Ralph P Schneider ◽  
Guntram Buesche ◽  
Jens Panse ◽  
Ulrich Germing ◽  
...  
Keyword(s):  
Stem Cell ◽  
Telomere Length ◽  
Peripheral Blood ◽  
Preliminary Analysis ◽  
Research Funding ◽  
Disease Duration ◽  
Treatment Initiation ◽  
Telomere Shortening ◽  
Length Analysis

Abstract Abstract 3809 Introduction: Myelodysplastic syndromes (MDS) are heterogeneous clonal stem cell disorders characterized by ineffective hematopoiesis and an increased risk for leukemic transformation. Lenalidomide (LEN) was found to be an effective treatment particularly in a subset of MDS patients with isolated 5q minus deletion (del5q). A high proportion of these patients show erythroid response with transfusion independence and even complete cytogenetic response (CCR). However, particularly in patients not responding to LEN, disease progression to acute leukemia is observed. Accelerated telomere length shortening is regularly observed in hematopoietic stem cell disorders with increased stem cell turnover and/or altered telomere maintenance. Dysfunctional telomeres have been found to play an important role in the development of chromosomal instability and malignant transformation. The aim of this study was to investigate telomere length as a potential predictive biomarker in MDS del5q patients treated with LEN with regard to disease progression and treatment response. Methods and Patients: Telomere length (TL) was determined using confocal Q-FISH on paraffin-embedded BM biopsies of 54 MDS patients enrolled in the LEMON5 study (NCT01081431). Criteria for study inclusion were isolated del5q, transfusion dependence of at least one unit per 8 weeks and IPSS low risk and intermediate-1. TL was analyzed in a blinded fashion on specimen obtained before treatment initiation with LEN, control biopsies of 11 patients with newly diagnosed Morbus Hodgkin without BM affection were used for age-adaption of TL. At the time of this preliminary analysis, the study is ongoing, initial clinical data were available for 94% (51/54) and detailed follow up data for 63% (34/54) of the patients with a median follow up of 22 months. Mean age of the MDS patients was 68.6 years (range 40–87) and average disease duration before enrolment was 2.9 years. Results: We found that TL of the 54 MDS patients was significantly shorter compared to the age-adjusted TL (−0.57 kb, p=0.02, n=54). Interestingly, analysis according to the respective IPSS showed significant shorter telomeres in the low risk group (−0.91 kb, p=0.04, n=27) than in the intermediate-1 group (−0.55 kb, p=0.24, n=19). Focusing on the peripheral blood counts, cut-off values were set according to the distribution pattern representing the approximate median value. Patients with ANC counts <2000/μl (−0.98 kb, p=0.03, n=27), haemoglobin values <9g/dl (−0.89 kb, p=0.02, n=26) and platelets counts <300/nl (−0.87 kb, p=0.01, n=27) had significantly shortened telomeres compared to the age-adjusted controls. In contrast, patients with ANC counts >2000/μl (0.06 kb, p=0.9, n=20), haemoglobin >9g/dl (−0.23 kb, p=0.23, n=25) and platelet counts >300/nl (−0.07 kb, p=0.58, n=24) did not differ from the age-adjusted TL. Furthermore, patients with a history of more than 2 years of MDS had significantly shortened age-adjusted telomere length (−0.94 kb, p=0.02, n=26), but that was not the case in patients with a short disease duration (<2 years; −0.32 kb, p=0.36, n=28). Interestingly, with regards to response to LEN, patients later achieving a CCR under LEN had significantly shortened TL at treatment initiation (−1.47 kb, n=14, p=0.005) whereas this was not the case in patients with no response, relapse or progressive disease during follow-up (−0.23 kb, n=20, p=0.62). Furthermore, correlation with treatment duration showed that patients receiving more than 12 cycles of LEN (in which 93%, i.e. 13/14 patients were responding) had significantly shorter telomeres before start of LEN (−1.41 kb, n=17, p=0.02) compared to the group of patients with less than 12 cycles (0.22 kb, n=14) in which 41%, i.e. 7/17 patients were responding. Conclusions: Patients with MDS and isolated del5q undergo significant telomere shortening. Using telomere length analysis on paraffin-embedded BM biopsies using confocal Q-FISH, we were able to identify a subgroup of patients with lower peripheral blood counts and accelerated TL shortening that seemed to preferentially profit from LEN treatment. In summary and pending further confirmation with longer follow up of this preliminary analysis within the ongoing LeMon5 study, we conclude that telomere length analysis may identify a distinct biological subentity of MDS del5q patients more likely to benefit from treatment with LEN. Disclosures: Germing: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brümmendorf:Celgene: Research Funding.

Dissecting the Complexity of Philadelphia-Positive Mutated Populations by Ultra-Deep Sequencing of the Bcr-Abl Kinase Domain: Biological and Clinical Implications

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 692-692 ◽  
Author(s):  
Simona Soverini ◽  
Caterina De Benedittis ◽  
Katerina Machova Polakova ◽  
Adela Brouckova ◽  
Fausto Castagnetti ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Kinase Domain ◽  
Mutation Status ◽  
Abl Kinase ◽  
Selection Of ◽  
Higher Sensitivity

Abstract Abstract 692 Background and Aims: In chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (ALL), tyrosine kinase inhibitor (TKI) therapy may select for drug-resistant Bcr-Abl mutants. Mutation status of resistant patients is usually investigated by Sanger sequencing (SS) of the Bcr-Abl kinase domain (KD). Novel ultra-deep sequencing (UDS) technologies allow to conjugate higher sensitivity with the unprecedented possibility to perform instant cloning of thousands of DNA molecules. We thus decided to take advantage of an UDS-based approach in order to: Methods: We retrospectively performed a longitudinal analysis of a total of 111 samples from 35 CML or Ph+ ALL patients who had received sequential treatment with multiple TKIs (two to four TKIs among imatinib, dasatinib, nilotinib, ponatinib) and had experienced sequential relapses accompanied by selection of TKI-resistant mutations. All samples had already been scored by SS; 74/111 (67%) were positive for one (n=33) or multiple (n=41) mutations. UDS of the Bcr-Abl KD was done using Roche 454 technology. UDS allowed to achieve a lower detection limit of at least 0.1% – as compared to 20% of SS. Results: Bcr-Abl KD mutation status was found to be more complex than SS had previously shown in 85/111 (77%) samples (representative examples are detailed in Table 1). In 33/74 (44%) samples known to harbour one or more mutations by SS, UDS revealed that up to four ‘minor’ mutations with 1–20% abundance were present in addition to the ‘dominant’ one(s). The type of mutations could easily be accounted for by TKI exposure history, since the majority were known to be poorly sensitive either to the current or to the previous TKI received. The higher degree of complexity was evident also when the clonal relationships of multiple mutations were reconstructed (Table 1). This revealed that identical mutations may be acquired in parallel by independent populations (e.g., one wild-type and one already harboring a mutation), via the same or different nucleotide changes leading to the same amino acid substitution (convergent evolution). In addition, longitudinal quantitative follow-up of mutated populations revealed that: Conclusions: Disclosures: Soverini: ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Luppi:CELGENE CORPORATION: Research Funding. Rosti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Martinelli:NOVARTIS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; PFIZER: Consultancy; ARIAD: Consultancy.

Reduced-Intensity Induction with Dasatinib Vs. Hypercvad + 2nd Generation TKIs with MRD-Guided Follow-up Therapy Leads to Comparable Rates of MRD-Negative Remission While Reducing Transfusions and Neutropenia in Ph+ ALL

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-44
Author(s):  
Jonathan Webster ◽  
Hua-Ling Tsai ◽  
Eric Gehrie ◽  
Tania Jain ◽  
Christopher S. Hourigan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Treatment Initiation ◽  
Advisory Board ◽  
High Dose ◽  
Allogeneic Bone ◽  
Advisory Committees ◽  
2Nd Generation ◽  
Reduced Intensity

Background: Reduced-intensity induction (RII) with imatinib yields comparable outcomes to HyperCVAD with imatinib with fewer induction deaths and an improved CR rate in Ph+ ALL (Chalandon. Blood. 2015). Dasatinib with steroids also produces excellent responses with little toxicity (Foa. Blood. 2011). Allogeneic bone marrow transplant (AlloBMT) remains the goal of therapy in Ph+ ALL based on contemporary trials with TKIs demonstrating improved survival in patients transplanted in CR1, and we have shown that transplant following induction with dasatinib yields better outcomes than with imatinib. Thus we implemented RII with dasatinib for the treatment of Ph+ ALL and compared to patients who received HyperCVAD with a 2nd generation TKI. Methods: Patients with newly diagnosed Ph+ ALL admitted to Johns Hopkins Hospital from September 2017-June 2020 underwent a 4-week RII with: vincristine 2 mg/d weekly, dexamethasone 40 mg PO weekly on days 1 and 2, and dasatinib 100 mg PO daily. CNS prophylaxis with IT MTX was given on day 8. Dexamethasone and vincristine were reduced by 50% for patients over age 70. Filgrastim was started on day 15 for patients without ANC recovery. Patients who received HyperCVAD with dose adjustments for age (Rausch et al. Cancer. 2020) from July 2011-June 2020 were included for comparison. Dasatinib 100 mg PO daily or nilotinib 400 mg PO BID were given with HyperCVAD at the discretion of the treating physician. Rituximab 375 mg/m^2 on days 1 and 8 was given based on CD20 status. Subsequent therapy after induction was not specifically mandated. Results: 21 patients received RII and 24 received HyperCVAD. The cohorts were comparable in terms of gender (38.1% female vs. 50%, p=0.55), age (median 49.8 vs. 50.3, p=0.33), age &gt;60 (33.3% vs. 29.2%, p&gt;0.99), median WBC at diagnosis (19 vs. 23.5, p=0.56), and the presence of decompensated DIC (fibrinogen &lt;150) prior to treatment initiation (4.8% vs. 8.3%, p&gt;0.99). Among the patients treated with HyperCVAD, 15 received dasatinib (62.5%) and 9 received nilotinib (37.5%). Rituximab use was balanced between the cohorts (61.9% vs. 58.3%, p&gt;0.99). Table 1 compares the time to ANC recovery &gt;500, transfusion requirements within 30 days of chemotherapy initiation, rates of decompensated DIC following treatment initiation, and the duration of inpatient hospitalization for induction. While the rates of decompensated DIC were similar in each cohort, patients treated with RII required fewer platelet and pRBC transfusions. ANC recovery was faster following RII, and only 5 patients (23.8%) received growth factor support. All patients achieved a hematologic response. There was one induction death with HyperCVAD (4.2%). Most patients received a subsequent cycle of high-dose (HD) MTX and Ara-C with TKI (76.2% following RII and 91.7% following HyperCVAD). The remaining patients treated with RII subsequently received HD MTX (14.2%) or blinatumomab (9.5%) with TKI due to co-morbidities. Among those patients treated with HD MTX and Ara-C, blinatumomab was given with TKI to 6 patients (37.5%) who initially received RII and 1 patient (4.5%) after HyperCVAD (p=0.03) due to persistent MRD. As shown in Figure 1, the incidence of MRD-negativity by multi-color flow cytometry (MFC) with a sensitivity of 10-4 at day 120 after treatment initiation was similar for RII (85.4%, 95% CI 64.8-97.1) versus HyperCVAD (86.7%, 95% CI 69.8-96.6). Among patients subsequently treated with HD MTX and Ara-C, 62.5% proceeded to alloBMT after RII with an additional 12.5% currently undergoing transplant evaluation, while 86.4% proceeded to alloBMT after HyperCVAD. The 1-year RFS and OS following RII were 87.9% (95% CI 59.6-96.8) and 100% compared to 87.5% (95% CI 66.1-95.8) and 95.8% (95% CI 73.9-99.4) following HyperCVAD. Conclusion: RII with dasatinib results in fewer transfusions and less myelosuppression compared to HyperCVAD with a 2nd generation TKI. More patients treated with RII received blinatumomab following high-dose MTX and Ara-C, but the rates of MRD-negativity were comparable between the two regimens. Thus RII with dasatinib followed by MRD-guided follow-up therapy facilitates MRD negative remissions with less toxicity than HyperCVAD. The vast majority of fit patients were able to proceed to alloBMT following either regimen. Transplant outcomes following dasatinib with induction are presented in our concurrent abstract demonstrating a 5-year RFS of 83% (95% CI 59.8-93.5). Disclosures Webster: Amgen: Consultancy; Pfizer: Consultancy. Jain:Bristol Myer Squibb: Other: for advisory board participation; CareDx: Other: Advisory Board; Takeda: Consultancy, Honoraria. Dalton:AbbVie: Research Funding; Eli Lilly: Research Funding. DeZern:Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria; MEI: Consultancy. Gojo:Genentech: Research Funding; Amphivena: Research Funding; Merck: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Bolanos-Meade:Incyte: Other: DSMB Fees. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. Ali:Celgene: Membership on an entity's Board of Directors or advisory committees. Borrello:Celgene: Research Funding; Aduro: Patents & Royalties; WindMIL Therapeutics: Other: Founder , Research Funding. Wagner-Johnston:ADC Therapeutics, Regeneron, CALIB-R, Verastem: Membership on an entity's Board of Directors or advisory committees. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levis:Menarini: Honoraria; Amgen: Honoraria; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding.

Real-World Treatments and Thrombotic Events in Polycythemia Vera Patients: A Retrospective Analysis between 2018-2019 in US Population

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Srdan Verstovsek ◽  
Ariel Han ◽  
Karin Chun Hayes ◽  
Tracy Woody ◽  
Frank Valone ◽  
...  
Keyword(s):  
High Risk ◽  
Real World ◽  
Blood Cells ◽  
Initial Treatment ◽  
Research Funding ◽  
Treatment Initiation ◽  
Low Risk ◽  
High Risk Patients ◽  
Risk Patients

BACKGROUND Polycythemia Vera (PV) is a rare myeloproliferative neoplasm associated with an increased production of red blood cells, white blood cells, and platelets. Most frequent treatment includes phlebotomy, hydroxyurea, interferon, and ruxolitinib. Current NCCN guideline recommends managing HCT levels to below 45%. The objective of this study was to determine real-world standards of care and patient characteristics, and to observe how treatment decisions vary by HCT level and thrombosis risk. METHODOLOGY We conducted a retrospective study using Symphony Health's longitudinal transactional healthcare claims database that includes prescription, medical and hospital claims across &gt; 4,900 US payers representing 86% of US lives. Eligible patients had at least one ICD-10 diagnosis code for PV and at least one of the treatments including phlebotomy, hydroxyurea, busulfan, interferon, and ruxolitinib between Jan 1, 2018 and Dec 31, 2019 (index period). For eligible patients, all prior treatment history initiated as far back as January 2010 was used to report therapy changes. Patients were also required to have at least one PV diagnosis within a year of treatment initiation and at least 2 HCT lab results during the index period. PV treatment changes and characteristics were studied. RESULTS Out of 28,306 patients with PV, 4,264 patients had HCT lab data for 2 years (index period). Median duration of follow-up was 854 days (range 98-3,373days). Patient therapy duration was from 1 to 9 years. Median patient age was 65 (range 11-94), with 1,451 (34%) patients aged less than 60, 2,813 (66%) 60 years or older, and a substantial male predominance (62% vs 38%). 1,247 (29%) patients were classified as Low Risk (age&lt; 60 with no TE history) and 3,017 (71%) patients as High Risk. Within the High-Risk group, 2,224 (52%) were age&gt;60 without prior TE, 204 (5%) were age&lt;60 with prior TE and 589 (14%) were age&gt;60 with prior TE. For Low Risk patients' initial treatment was phlebotomy alone (85%) and a total of 73% of all Low Risk patients remained on phlebotomy alone. For High Risk patients' initial treatment was phlebotomy alone (60%) and 43% all of High-Risk patients remained on phlebotomy alone (Figure 1). The median HCT prior to treatment initiation was 52.9% and 48% during treatment. 936 (22%) patients achieved NCCN treatment guidelines with HCT levels always remaining under 45%, and 1,226 (29%) patients had HCT levels controlled between 45% and 50%. However, 2,102 (49%) patients had some or all HCT levels&gt; 50% (Figure 2). With the most recent lab test, 2,180 (51%) of patients still had HCTs above 45% and 804 (19%) were still above 50%. In a sub-cohort of 653 High Risk patients with a prior TE and up to 5 years of follow up, 236 (36%) had at least one other TE; for the 1,774 High Risk patients who did not have the history of thrombosis, 161(9%) had at least one TE (Table 2). The most common TE since treatment began in patients with prior TE were deep vein thrombosis (n= 92 patients, 14%) and stroke (n= 95 patients, 15%). Among High Risk patients (n=397) who had another thrombotic event, 180 (45%) were treated by phlebotomy only and never switched to any other therapies. CONCLUSIONS Despite currently available treatments in US, patients' HCT level after treatment were higher than recommended as per guidelines. Failure to maintain HCT less than 45% increases the risk of future thrombotic events as shown by 36% of patients with prior TE experiencing another TE within the next 5 years. Disclosures Verstovsek: Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; CTI Biopharma Corp: Research Funding. Han:Protagonist Therapeutics: Consultancy. Chun Hayes:Protagonist: Consultancy. Woody:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Gupta:Protagonist: Current Employment.

scholarly journals Association between Quality of Response and Outcome in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1873-1873
Author(s):  
Paolo Strati ◽  
Mariela Sivina ◽  
Ekaterina Kim ◽  
Michael J. Keating ◽  
William G. Wierda ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Treatment Initiation ◽  
Treatment Discontinuation ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Genetics Research ◽  
Baseline Characteristics

Abstract Introduction. In the context of chemoimmunotherapy, complete remission (CR) is more common and is associated with improved survival in patients with chronic lymphocytic leukemia (CLL). CR is less frequent in CLL patients treated with ibrutinib, and the prognostic significance of achieving CR with ibrutinib is indeterminate. Methods. We prospectively analyzed 208 CLL patients treated on a phase 2 study (NCT02007044) of first-line (deletion 17p only; n=27) or salvage ibrutinib (n=181), with or without rituximab, between 12/2013 and 01/2018. Response was assessed by international workshop on CLL 2018 guidelines. Categorical variables were compared using the χ2 or Fisher exact tests. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression and/or death, and Kaplan-Meier curves compared using the log-rank test. A landmark analysis at median time of CR achievement (best response) was performed for PFS. Results. After a median follow-up of 34 months (range, 3-48 months), response was evaluable in 194 patients, overall response rate (ORR) was 99%, and CR rate was 24%, with negative minimal residual disease (MRD) in 3% of patients; median time to response was 10 months (range, 3-45 months) and median time to CR was 21 months (5-45 months). None of the patients' baseline characteristics associated with achievement of CR (Table). Among the 47 patients in CR, 7 (15%) discontinued treatment, after a median time from treatment initiation of 19 months (range, 10-39); the main cause of discontinuation was toxicity (5 patients), with second cancer (metastatic melanoma) and disease progression prompting treatment discontinuation only in 2 patients. Among the 145 patients in PR, 50 (34%) discontinued treatment, after a median time from treatment initiation of 14 months (range, 4-45 months); while the main cause of discontinuation was again toxicity (26 patients), 2nd cancers and progressive disease prompted treatment discontinuation in 5 and 14 patients, respectively. Remaining causes of treatment discontinuation among patients in PR were loss to follow-up (3 patients) and consolidation therapy (2 patients). Median PFS was not reached and 28 patients (13%) progressed and/or died. Achievement of CR significantly associated with prolonged PFS (4-year PFS 98% vs 78%, p=0.03)(Figure). The association between CR and prolonged PFS was also confirmed on a landmark analysis (21 months)(p=0.05). Among baseline characteristics shown in the Table, the only factor associated with prolonged PFS was absence of complex karyotype (4-year PFS 80% vs 40%, p=0.05). Median OS has not been reached and 16 (8%) patients have died; of these, only 1 patient was in CR (and cause of death was metastatic melanoma), whereas the remaining 15 were in PR. Among patients in PR, causes of death were: infections in 7 patients, 2nd cancers in 2 patients, Richter transformation in 2 patients and other in 4 patients (small bowel obstruction, colon perforation, intracranial hemorrhage, bradyarrhythmia). Conclusions. This is the first study showing that achievement of CR is a desirable endpoint for patients with CLL treated with ibrutinib, associating with prolonged PFS. Our results support the development of future combination studies, aimed at achieving higher rates of CR in patients treated with ibrutinib. Figure. Figure. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Jain:Infinity: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Adaptive Biotechnologies: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Long-Term Follow-up of Follicular Lymphoma (FL) Patients (pts) Demonstrating Undetectable Minimal Residual Disease (MRD) Using a Next-Generation Based DNA Assay: Support for FL As a Curable Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2813-2813
Author(s):  
Maryam Sarraf Yazdy ◽  
Umair Jarral ◽  
Chao Yin ◽  
Frank Kuhr ◽  
Allison P. Jacob ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Board Of Directors ◽  
Research Funding ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Allogeneic Bone ◽  
Next Generation ◽  
Advisory Committees ◽  
Generation Sequencing

BACKGROUND FL is the most common indolent non-Hodgkin lymphoma (NHL). While very responsive to therapy, it has been considered incurable. Nonetheless, pts remaining in remission >24 months appear to have a survival comparable to an age-matched population without NHL (Casulo et al, J Clin Oncol, 33:2516, 2015), and some are free of disease for many years and die from unrelated events. METHODS Adult pts were accrued from the Lombardi Comprehensive Cancer Center Lymphoma clinic. Pts were required to have histologically confirmed FL or transformed FL that was previously treated resulting in a complete remission, and were required to be free of progression at any time > 24 months following completion of treatment without intervening therapy. Original diagnostic samples were retrieved and subjected to clonality assessment using Adaptive's next generation sequencing (NGS) MRD assay , a research version of clonoSEQ®; (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci as well as translocations in Bcl1/2 IgH. Lymph node biopsy from time of original diagnosis was assessed to identify trackable clonotypes, which were found in 37/43 patients. Peripheral blood was assayed upon entry onto the study and every 6 months thereafter by the NGS-MRD assay to monitor MRD. Samples are being collected every 6 months during follow-up, and the results are being correlated with clinical outcome. RESULTS Of the 60 eligible pts who signed consent 41% were females, with a median age at diagnosis of 56 yrs (21-75) and median age at treatment of 56 years (21-75). Twenty six had received one prior line of treatment (LOT), 4 had 2, 6 had 3, and 1 had 5. The most common immediately prior line of therapy included bendamustine and rituximab (BR, n=16); rituximab, cyclophosphamide, adriamycin, vincristine, prednisone (RCHOP, n=6); double-monoclonal antibody containing regimens(rituximab-galiximab; rituximab-epratuzumab (n=3)), radioimmunotherapy (n=3), and allogeneic bone marrow transplant (n=2). The media follow-up since the start and completion of most recent therapy was 62 months (range 25-183 and 32-193, respectively). Of the 60 pts for whom original biopsy slides were obtainable, the quality was inadequate to amplify the DNA in 18. In another 5 pts, the sample was polyclonal and a dominant rearrangement could not be identified. In 32 of the 37 pts (86.5%), samples were negative at enrollment to this study at a level of detection of 10-5. By prior LOT, samples were negative in 25 of 26 following 1st line; 1 of 4 following 2nd line; 5 of 6 following 3rd line; and in the one pt after 5th line. In all but 1 pt, the assay has remained negative on subsequent determinations as shown in the spider plot (Fig 1). The 5 positive patients had been followed for a median of 85 (56-118) months. Additional follow-up is underway to determine if positive pts will eventually relapse. CONCLUSIONS These data are the first to demonstrate that a high proportion of FL pts in a prolonged clinical remission have undetectable DNA by sensitive next generation sequencing, without evidence of clinical progression, and are potentially cured of their disease. Figure 1 Disclosures Yazdy: Bayer: Honoraria, Speakers Bureau; Genentech: Research Funding; Abbvie: Consultancy; Octapharma: Consultancy. Kuhr:Adaptive Biotechnologies: Employment, Other: shareholder. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Cheson:Epizyme: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding.

TP53 Mutated MDS Patients Respond Equally to Hypomethylating Agents but Have Significantly Shorter Response Duration Compared to Patients with Wild Type TP53

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1681-1681 ◽  
Author(s):  
Koichi Takahashi ◽  
Hagop M. Kantarjian ◽  
Keyur Patel ◽  
Carlos E Bueso-Ramos ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Prognostic Impact ◽  
Hypomethylating Agents ◽  
Complex Karyotype ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Duration Of Response

Abstract Background: Prognostic impact of TP53 mutations has been well described in MDS. However little is known about predictive impact on response to hypomethylating agents (HMA). Aim: To determine predictive impact of TP53 mutation on response to frontline HMA therapy in MDS. Methods: Bone marrow samples from 168 patients with untreated MDS were screened for TP53 mutation by next generation sequencing platform. All patients were treated with upfront 5-azacitidine or decitabine based HMA therapy. 13 of them had longitudinal follow up of TP53 mutation after HMA therapy. Results: 38 patients (23%) had TP53 mutations. At baseline, TP53 mutated patients were significantly more neutropenic (P = 0.02), thrombocytopenic (P = 0.008), and had higher bone marrow blast (P = 0.006). TP53 mutation was significantly associated with complex karyotype (P < 0.001), monosomal karyotype (P < 0.001), and del 17p/-17 (P < 0.001). There was a trend toward mutual exclusivity between splicing pathway gene mutations and TP53 mutation (P = 0.07). Complete response (CR) and overall response (OR) to HMA therapy was observed in 34% and 45% of TP53 mutated patients, respectively, and there was no statistical difference from wild type patients (P = 0.38 and P = 0.13). Time to achieve response was also similar between TP53 mutated and wild type patients (P = 0.2). However, TP53 mutated patients had significantly shorter CR duration compared to wild type patients (6.3 months versus 28.5 months, P = 0.001). 11 out of 13 patients who had longitudinal follow up of TP53 mutation were found to have the same persistent TP53 mutation when they lost response to HMA therapy. TP53 mutated patients had worse overall survival (P <0.001) and prognostic impact of TP53 mutation was significant after adjusting for complex karyotype or IPSS-R risk. Conclusion: MDS patients with TP53 mutations equally respond well to HMA therapy compared to WT patients. However, duration of response is significantly shorter than WT patients, which translates into worse overall survival. Longitudinal follow up showed persistence of the same TP53 clone after HMA therapy. Novel therapeutic strategy to improve duration of response in TP53 mutated MDS is urgently needed. Disclosures DiNardo: Novartis: Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding.

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