Tailored Approaches for Refined Prognostication in Chronic Lymphocytic Leukemia Patients with Mutated Versus Unmutated Immunoglobulin Receptors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3199-3199
Author(s):  
Panagiotis Baliakas ◽  
Theodoros Moysiadis ◽  
Anastasia Hadzidimitriou ◽  
Aliki Xochelli ◽  
Mattias Mattsson ◽  
...  
Keyword(s):  
High Risk ◽  
Low Risk ◽  
Rank Test ◽  
P Value ◽  
Paired Comparisons ◽  
Intermediate Risk ◽  
Log Rank Test ◽  
Recurrent Mutations ◽  
Prognostic Indices ◽  
Very High

Abstract The classification of CLL patients according to the somatic hypermutation status (SHM) of the immunoglobulin heavy variable (IGHV) genes, namely mutated (M-CLL) versus unmutated (U-CLL), reflects fundamental differences in disease biology and clinical course. Realizing this, here we followed a compartmentalized approach and addressed the issue of prognostication separately for M-CLL and U-CLL. In a multi-institutional cohort of 2366 patients [M-CLL, n=1364 (58%); U-CLL, n=1002 (42%)] consolidated within ERIC, the European Initiative in CLL, we assessed the clinical impact of 'traditional' (age and clinical stage at the time of diagnosis, gender, CD38 expression, FISH detected abnormalities included in the Döhner hierarchical model of cytogenetic aberrations), and novel prognosticators (recurrent mutations within the TP53, SF3B1, NOTCH1, MYD88, and BIRC3 genes; IGHV gene usage; membership in stereotyped subsets) within M-CLL and U-CLL. Our statistical approach was based both on Cox regression models and recursive partitioning algorithms; internal validation was performed via bootstrapping procedures. Given the retrospective nature of our study, time-to-first-treatment (TTFT) was the primary endpoint. As expected, M-CLL exhibited significantly longer TTFT compared to U-CLL [median TTFT: not yet reached (M-CLL) vs 1.9 years (95% CI: 0.01-12.3 years, U-CLL), p<0.0001]. Advanced clinical stages (Binet B-C) were associated with shorter TTFT in both M-CLL and U-CLL; a significantly worse outcome was also identified for Binet C versus Binet B cases (p<0.0001). Binet A patients received our special focus, representing 90% and 67% of M-CLL and U-CLL studied cases, respectively. Amongst Binet A M-CLL cases, TP53 aberrations [TP53abs, deletions of chromosome 17p, del(17p) and/or TP53 mutations], stereotyped subset #2 membership and trisomy 12 were identified as equally adverse prognostic indicators [median TTFT: 5.5 (95% CI: 0.2-12.8), 4 (95% CI: 0.6-6.8) and 7.3 (95% CI: 0.7-13.4) years, respectively; p-value: non-significant when applying the log-rank test for all paired comparisons); of note, TP53abs were mutually exclusive with the other two features. Amongst Binet A U-CLL cases, TP53abs, SF3B1 mutations and deletion of chromosome 11q [del(11q)] had an overall similar adverse impact [median TTFT for TP53abs, SF3B1 mutations and del(11q): 1.8 (95% CI: 0.01-4.4), 2 (95% CI: 0.01-7.7) and 2.1 (95% CI: 0.01-8.1) years, respectively, p-value: non-significant when applying the log-rank test for all paired comparisons]. Within the remaining Binet A U-CLL cases [i.e. those lacking TP53abs and/or SF3B1 mutations and/or del(11q)], the only parameter associated with shorter TTFT was male gender (median TTFT: 3.5 years, 95% CI: 0.5-8.1 years). Based on these findings, we developed two prognostic indices for assessing TTFT tailored specifically to M-CLL and U-CLL, respectively. Within M-CLL (Figure 1A), 4 subgroups were identified: (i) very high risk: Binet C with identical 5- and 10-year treatment-probability (TP) of 92%; (ii) high risk: Binet B, 5y-TP and 10y-TP: 64% and 84%, respectively; (iii) intermediate risk: Binet A with one of the following: TP53abs or +12 or subset #2 membership, 5y-TP and 10y-TP: 40% and 55%, respectively; and (iv) low risk: Binet A nonTP53abs/+12/subset#2, 5y-TP and 10y-TP: 12% and 25%, respectively. Within U-CLL (Figure 1B), 5 subgroups were identified: (i) very high risk: Binet C with 5- and 10-year TP of 100%; (ii) high risk: Binet B, identical 5y-TP and 10y-TP: 90% and 100%, respectively; (iii) intermediate risk: Binet A with one of the following: TP53abs or SF3B1 mutations or del(11q), 5y-TP and 10y-TP: 78% and 98%, respectively; (v) low risk: Binet A, male nonTP53abs/SF3B1mut/del(11q), 5y-TP and 10y-TP: 65% and 85%, respectively and (iv) very low risk: Binet A, female nonTP53abs/SF3B1mut/del(11q), 5y-TP and 10y-TP: 45% and 65%, respectively. In conclusion, we identified clinicobiological parameters with distinct prognostic implications for M-CLL and U-CLL. These parameters were used in order to develop prognostic indices tailored to SHM status that were found capable of distinguishing subgroups with markedly different outcomes. We argue that such a compartmentalized approach may supersede previous attempts, thus overcoming the pronounced heterogeneity of CLL and optimizing prognostication. PB and TM contributed equally as first authors Figure 1 Figure 1. Disclosures Rosenquist: Gilead Sciences: Speakers Bureau.

scholarly journals Impact of Thromboembolism on Overall and Event-Free Survival in Children with Acute Lymphoblastic

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 51-52
Author(s):  
Marie-Claude Pelland-Marcotte ◽  
Ketan Kulkarni ◽  
Uma Athale ◽  
Jason Pole ◽  
Leonardo R. Brandao ◽  
...  
Keyword(s):  
High Risk ◽  
Cancer Diagnosis ◽  
Risk Group ◽  
Low Risk ◽  
Rank Test ◽  
Event Free Survival ◽  
Free Survival ◽  
Log Rank Test ◽  
Life Threatening ◽  
Very High

Introduction: Thromboembolism (TE) is a well-known complication of cancer and its treatments. The impact of TE on survival outcomes remains unclear, especially in children. We assessed whether TE development was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). Methods: We performed a population-based retrospective cohort study using the national registry Cancer in Young People Canada (CYP-C). Children 0-&lt;15 years of age diagnosed with ALL (2000-2018) and treated at one of 12 Canadian pediatric centers outside of Ontario were included. OS was defined as the time between the date of cancer diagnosis and death and, EFS, as the time between the date of cancer diagnosis and the date of relapse, subsequent malignancy or death (whichever came first). Patients were categorized as to whether they experienced a radiologically-confirmed TE during treatment graded 3, 4 or 5 as per the Common Terminology Criteria for Adverse Events v.4 (i.e. requiring medical treatment, life-threatening or fatal). Only TEs that occurred before relapse or subsequent malignancy were considered. The Kaplan-Meier survival method estimated the 5-year OS and EFS of children with TE compared to those without TE. Univariate and multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of death or an event between groups, adjusted for age, sex, and leukemia risk group. A sub-analysis stratified the analysis by leukemia risk group. Results: The study included 2,208 children (median age: 4 years [interquartile range: 2-7 years], 54.9% male). Precursor B-cell ALL was the most common diagnosis (1,789, 89.1%). Patients were stratified as standard/low risk ALL in 58.0% of cases, and high/very high risk ALL in 42.0%. Of these, 121 (6.0%) developed a TE, at a median time of 100 days (interquartile range: 30-183 days) after cancer diagnosis. Eight patients (0.4%) had a life-threatening or fatal TE. Patients with TE were more likely to be aged 10 years or older, to present with T-cell ALL, and to have high risk leukemia. The 5-year OS (95% CI) of patients with and without TE was 80.2% (72.9-87.5%) and 93.7% (92.5-94.9%) respectively (log-rank test: p&lt;0.001, Figure 1). The adjusted HR (95% CI) of death in children with TE was 2.09 (1.33-3.27, p=0.001). Similarly, as shown in Figure 2, the 5-year EFS (95% CI) of patients with and without TE was 68.7% (59.7-77.7%) and 88.6% (87.1-90.1%), respectively (log-rank test: p&lt;0.001). The adjusted HR (95% CI) of an event was 2.01 (1.39-2.90, p&lt;0.001). When stratified by leukemia risk group, no statistically significant difference was seen in standard/low risk ALL for both OS and EFS but TE was associated with a significantly lower OS and EFS in children with high/very high risk ALL (Table 1). In this group, the increased risk of death was attributable to both deaths following relapsed disease (HR [95% CI]: 2.37 [1.39-4.04]) and death not following relapse (HR [95% CI]: 2.93 [1.35-6.35]). Sensitivity analyses in which 1) patients with very high risk ALL were removed and 2) only grade 3 or 4 TE were considered showed similar results. Conclusions: Clinically relevant TE led to a statistically significant reduction in OS and EFS in children with high risk/very high risk leukemia. Further research is needed to assess whether TE prevention may improve anti-cancer outcomes. Disclosures Brandao: Boehringer Ingelheim: Other: Member of a paediatric expert working group.

P1952Value of GRACE risk score in risk stratification in acute coronary syndrome patients undergoing PCI in the Global Leaders study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Komiyama ◽  
P Chichareon ◽  
C Hamm ◽  
P Juni ◽  
M Valgimigli ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Risk Group ◽  
Low Risk ◽  
Rank Test ◽  
P Value ◽  
Moderate Risk ◽  
Grace Risk Score ◽  
Log Rank Test ◽  
All Cause Mortality

Abstract Aims We sought to evaluate the value of GRACE risk score in stratifying acute coronary syndrome patients undergoing percutaneous coronary intervention in the Global Leaders study. Methods Global Leaders study was a prospective, multi-center, open-label, all-comers, randomized controlled trial comparing ticagrelor monotherapy after 1 month of dual antiplatelet therapy (DAPT) as experimental therapy with aspirin monotherapy after 12 months of conventional DAPT (reference therapy) in patients who received PCI with biolimus-A9 eluting stent. We assessed the predictive value of GRACE risk score in ACS patients undergoing PCI in the present analysis. Patients were stratified according to GRACE risk score into low (1–108), moderate (109–140), High (141–372) risk group. Clinical outcomes at 2 years after PCI were assessed and compared among risk groups. Interaction between GRACE risk score and antiplatelet regimen were analyzed by the interaction term in Cox model. Results GRACE risk score was calculated from 8 clinical parameters at presentation. Among ACS patients, 1664 patients were categorized in low risk group, 2903 patients were in moderate risk group, and 2028 patients were in high risk group. The rate of all-cause mortality, any stroke, patient-oriented composite endpoint (POCE) were highest in the high-risk group at 2 years (All-cause mortality; low risk 1.4%, moderate risk 2.5%, high risk 6.1%, log rank test p value <0.0001, any stroke; low risk 0.7%, moderate risk 1.0%, high risk 2.0%, log rank test p value 0.001, POCE; low risk 12.4%, moderate risk 11.9%, high risk 16.61%, log rank test p value <0.0001). The rate of myocardial infarction, all revascularization and definite or probable stent thrombosis were not different among three groups. There was no interaction between GRACE risk score and treatment regimen on clinical outcomes at 2 years. Conclusion GRACE risk score is valuable in identifying ACS patients with highest risk of all-cause mortality, any stroke and POCE at 2 years after PCI. In ACS, ticagrelor monotherapy did not improve the outcomes at 2 years in the three strata of the GRACE risk score.

Do Unexpected and Cryptic FISH Lesions Of Chromosomally Normal MDS Patients Have Any Prognostic Relevance?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1549-1549
Author(s):  
Paolo Bernasconi ◽  
Irene Dambruoso ◽  
Marina Boni ◽  
Paola Maria Cavigliano ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Low Risk ◽  
Disease Stage ◽  
Intermediate Risk ◽  
Disease Evolution ◽  
Prognostic Relevance ◽  
Increased Risk ◽  
Very High ◽  
Disease Specific

Abstract Conventional cytogenetic (CC) still remains a mandatory step in the routine diagnostic work-up of every MDS patient (pt), is one of the major determinant of disease outcome and guides potential treatment decisions. However, CC is not informative in about 50% of chromosomally normal (CN) pts and provides limited information in those with very rare defects even if the revised IPSS cytogenetic categories have tried to overcome this drawback. More sensitive techniques (aCGH, SNP-a and NGS), still used in the research setting only, suggest that CN pts may instead contain novel unexpected chromosomal lesions which prognosis is still undefined. Thus, the principal goal of our study was to establish whether FISH with disease specific probes (i.e. for chromosomal regions most commonly affected in MDS) along with non-disease specific probes (i.e. for regions which alteration in MDS has been demonstrated by aCGH only) may effectively unmask clonal cryptic defects. Other aims were to establish the nature of these defects, to identify the potentially targeted genes and to estimate their possible prognostic relevance. The one-hundred twenty-seven consecutive CN MDS pts of the present study came to our observation in the period January 2003-December 2012. They were forty-nine females and seventy-eight males, median age 66 years (range 24-88). Twenty-one pts were diagnosed as RARS, 29 as RA, one as CRMDS, one as U-MDS, 25 as RCMD, 26 as RAEB-1 and 24 as RAEB-2. On CC 122 pts presented a normal karyotype and five no mitotic figures. Considering the revised IPSS score, 62 pts were considered very low-risk, 32 low-risk, 23 intermediate risk, 8 high-risk and 2 very high-risk. Median follow-up was 22 months (range 1-90). At the time of the study nine pts have died. FISH probes were chosen based on the frequency of their involvement in MDS and their Mb position determined using UCSC genome browser on Human Mar. 2003 assembly. They were obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), labelled and applied as previously described. These probes were: RP11-912D8 (19q13.2); RP11-196P12 (17q11.2); RP11-269C4 (14q12); RP11-351O1 (10q21.3); RP11-144G6 (10q11.2); RP11-122A11 (7q34); RP11-951K18 (5q13.1); RP11-101K5 (4p14); RP11-544H14 (2q33). i-FISH cut-off values were fixed at 10%. Thirty-one pts (24.4%) presented at least a single defect, always represented by deletions or gains of chromosomal material. Among them 8 pts (25.8%) presented at least two defects. Bands most commonly targeted by deletions/amplifications were 19q13.2 (61.3%), 14q12 (32.2%), 17q11.2 (16.1%), 5q13.1 (12.9%), 7q34 (12.9%), 4p14 (9.6%). Deletions of bands 10q11.2, 10q21.3 and 2p33 were more rare. As the RMD-1 gene, involved in DNA double strand breaks and homologous recombination, maps at band 19q13.2, the most commonly deleted chromosomal area, additional molecular tests are being developed to analyse this gene. An abnormal FISH pattern was observed in 2/21 (9.5%) RARS, in 7/29 (24.1%) RA, in 5/25 (20.0%) RCMD, in 8/26 (30.6%) RAEB-1 and in 9/24 (37.5%) RAEB-2. Considering IPSS, an abnormal FISH pattern was revealed in 7/62 (11.3%) very low-risk, in 8/32 (25%) low-risk, in 10/23 (43.4%) intermediate risk, in 5/8 (62.5%) high-risk and in 1/2 very high-risk patients. Disease evolution occurred in a total of 34 pts (3 RARS, 7 RA, 5 CRMD, 11 RAEB-1 and 8 RAEB-2), 16 (one RARS, 3 RA, 2 CRMD, 6 RAEB-1 and 4 RAEB-2) with an abnormal FISH pattern. All the 8 patients with at least two chromosomal deletions experienced disease progression. In conclusion, i) FISH reveals novel unexpected karyotype defects, most commonly deletions pinpointing genes involved in DNA repair, in about 24.4% of CN MDS; ii) band 19q13.2 deletion is the most common defect, frequently associated with disease evolution; ii) an abnormal FISH pattern is correlated with an advanced disease stage and an intermediate/high revised IPSS score; iii) >two lesions are associated with an increased risk of disease progression. Disclosures: No relevant conflicts of interest to declare.

Disease-Attributable Mortality in the Myelodysplastic Syndromes (MDS): A Study from the Spanish MDS Cooperative Group (GESMD)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1672-1672
Author(s):  
Meritxell Nomdedeu ◽  
Xavier Calvo ◽  
Dolors Costa ◽  
Montserrat Arnan ◽  
Helena Pomares ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Mortality Rates ◽  
Low Risk ◽  
Attributable Mortality ◽  
Risk Category ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Very High ◽  
Risk Categories

Abstract Introduction: The MDS are a group of clonal hematopoietic disorders characterized by blood cytopenias and increased risk of transformation into acute myeloid leukemia (AML). The MDS predominate in old people (median age at diagnosis > 70 years) so that a fraction of the observed mortality would be driven by age-related factors shared with the general population rather than the MDS. Distinguishing between the MDS-related and unrelated mortality rates will help better assessment of the population health impact of the MDS and more accurate prognostication. This study was aimed at quantifying the MDS-attributable mortality and its relationship with the IPSSR risk categories. Methods: The database of the GESMD was queried for patients diagnosed with primary MDS after 1980 according to the WHO 2001 classification. Patients with CMML, younger than 16 years or who lacked the basic demographic or follow-up data were excluded. Relative survival and MDS-attributable mortality were calculated by the cohort method and statistically compared by Poisson multivariate regression as described by Dickman (Stat Med 2004; 23: 51). Three main parameters were calculated: the observed (all-cause) mortality, the MDS-attributable mortality (both as percentage of the initial cohort), and the fraction of the observed mortality attributed to the MDS. Results: In total, 7408 patients met the inclusion criteria and constitute the basis for this study. Among these patients, 5307 had enough data to be classified according to the IPSSR. Median age was 74 (IQR: 16-99) years and 58 % were males. The most frequent WHO categories were RAEB, type I or II (29% of cases), RCMD (28%), and RA with ring sideroblasts (16%). Most patients (72%) were classified within the very low and low risk categories of the IPSSR. At the study closing date (December 2014), 1022 patients had progressed to AML, 3198 had died (974 after AML) and 3210 were censored alive. The median actuarial survival for the whole series was 4.8 (95% CI: 4.6-5.1) years and 30% of patients are projected to survive longer than 10 years. The overall MDS-attributable mortality at 5 years from diagnosis was 39%, which accounted for three-quarters of the observed mortality (51%, figure). The corresponding figures at 10 years for the MDS-attributable and observed mortality were 55% and 71%, respectively. According to the IPSSR, the 5-year MDS-attributable mortality rates was 19% for the very low risk category, 39% (low risk), 70% (intermediate risk), 78% (high risk), and 92% (very high risk). On average, the incidence rate ratio for the MDS-attributable mortality increased 1.9 times (95% CI: 1.7-2.3, p<0.001) as the IPSSR worsened from one to the next risk category. The fraction of the observed mortality attributed to the MDS was 0.55 for the very low risk category, 0.79 (low risk), 0.93 (intermediate risk), 0.96 (high risk), and 0.99 (very high risk). After distinguishing between AML-related and unrelated mortality, the 5-year MDS-attributable mortality not related to AML was 10% for the very low risk category, 20% (low risk), 33% (intermediate risk), 42% (high risk), and 44% (very high risk). By comparing these figures with the above ones, we could estimate that about 50% of the MDS-attributable mortality was AML-unrelated and that such fraction kept nearly constant across the five IPSSR categories. Conclusions: About three-quarters of the mortality observed in patients with MDS is caused by the disease, the remaining one-quarter being due to MDS-independent factors shared with the general population. The MDS-attributable mortality increases with the IPSSR risk category, from half the observed mortality in the very low risk to nearly all the mortality observed in the high and very high risk groups. Half the MDS-attributable mortality is driven by factors unrelated to leukemic transformation, a proportion that keeps constant across the five IPSSR risk categories. Disclosures Valcarcel: AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ramos:AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

A 13-Glycosylation Gene Signature in Multiple Myeloma Can Predicts Survival and Identifies Candidates for Targeted Therapy (GiMM13)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4423-4423 ◽  
Author(s):  
Caoilfhionn Connolly ◽  
Alokkumar Jha ◽  
Alessandro Natoni ◽  
Michael E O'Dwyer
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
Rank Test ◽  
P Value ◽  
Log Rank Test ◽  
Novel Approach

Abstract Introduction Advances in genomics have highlighted the potential for individualized prognostication and therapy in multiple myeloma (MM). Previously developed gene expression signatures have identified patients with high risk (Kuiper et al, Blood 2016) however, they provide few insights into underlying disease biology thereby limiting their use in informing treatment decisions. Glycosylation is deregulated in MM (Glavey et al), and potential consequences include altered cell adhesion, signaling, immune evasion and drug resistance. In this study we have utilized RNA sequencing data from the IA7 CoMMpass cohort to characterize the expression profile of genes involved in glycosylation. This represents a novel approach to identify a distinct molecular pathway related to outcome, which is potentially actionable. Methods A pathway based approach was adopted to evaluate genes implicated in glycosylation, including the generation of selectin ligands. A literature review and KEGG pathway analysis of pathways relating to O-glycans, N-glycans, sialic acid metabolism, glycolipid synthesis and metabolism was completed. RNA Cufflinks-gene level FPKM expression of 458 patients enrolled in the IA7 cohort of the Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) were analysed as derivation cohort. We developed expression cut-offs using a novel approach of adjusted existing linear regression model to define the gene expression cut-off by applying 3rd Quartile data (q1+q2/2-qmin). The analysis of overall survival (OS) was completed using adjusted 'kpas' R-package according to our cut-off model. Association between individual transcripts and OS was analyzed with log-rank test. Genes with p-value <0.2 were used in subsequent prioritization analysis. This cut-off methodology was employed to define the nearest neighbor for a gene for Gene Set Enrichment Analysis (GSEA). As far as 4th neighbor above and below the cut off was used to have centrally driven gene selection method for prioritization. The gene signature was validated in GSE2658 (Shaughnessy et al) dataset. Results Initial analysis yielded 184 prospective genes. 147 were significant on univariate analysis. Following further prioritization of these genes, we identified thirteen genes that had significant impact upon outcomes (GiMM13). Figure 1 reveals that GiMM13 signature has a significant correlation with inferior OS (HR 4.66 p-value 0.022). The prognostic impact of stratifying GiMM13 positive (High risk) or GiMM13 negative (Low risk) by ISS stage was evaluated. In Table 1. Kaplan Meier estimates generated for GiMM13 (High) or GiMM13 (Low) stratified by ISS are compared statistically using the log rank test. The prognostic ability of GiMM13 to synthesize distinct subgroups relative to each ISS stage is shown in Figure 2. ISS1-Low is the the lowest risk group with best prognosis. Hazard ratios relative to the ISS1-Low group were 1.8, p-value 0.029 (ISS2-Low), 2.1, p-value 0.031 (ISS3-Low), 4.3, p-value 0.04 (ISS1-HR), 5.9, p-value 0.039 (ISS2-HR) and 3.1, p-value 0.001 (ISS3-HR). The GiMM13 signature enhances the prognostic ability of ISS to identify patients with inferior or superior outcomes respectively. Conclusion While the therapeutic armamentarium for MM has expanded considerably, the significant molecular heterogeneity in the disease still poses a significant challenge. Our data suggests aberrant transcription of glycosylation genes, involved predominantly in selectin ligand synthesis, is associated with inferior survival outcomes and may help identify patients likely to benefit from treatment with agents targeting aberrant glycosylation, e.g. E-selectin inhibitor. Consistent with recent findings in chemoresistant minimal residual disease (MRD) (Paiva et al, Blood 2016), it would appear that O-glycosylation, rather than N-glycosylation is most significantly implicated in this biological processes conferring inferior outcomes. In conclusion, using a novel pathway-based approach to identify a 13-gene signature (GiMM13), we have developed a robust tool that can refine patient prognosis and inform clinical decision-making. Acknowledgment These data were generated as part of the Multiple Myeloma Research Foundation Personalized Medicine Initiatives (https://research.themmrf.org and www.themmrf.org). Disclosures O'Dwyer: Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Are men with favorable intermediate-risk prostate cancer candidates for active surveillance?

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 82-82
Author(s):  
Ann Caroline Raldow ◽  
Danjie Zhang ◽  
Ming-Hui Chen ◽  
Michelle H. Braccioforte ◽  
Brian Joseph Moran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Active Surveillance ◽  
Locally Advanced ◽  
Low Risk ◽  
P Value ◽  
High Dose ◽  
Intermediate Risk ◽  
Increased Risk ◽  
Risk Prostate Cancer

82 Background: Active surveillance (AS) is considered appropriate for patients with low-risk prostate cancer (PC) and a life expectancy of at least 10 years. However, with grade migration following the 2005 International Society of Urologic Pathology consensus conference, AS may also be an initial option for men with favorable intermediate-risk PC. We estimated and compared the risk of PC-specific mortality (PCSM) following high dose radiation therapy and androgen deprivation therapy as appropriate amongst men with low, favorable intermediate, unfavorable intermediate, and high-risk PC. Methods: The study consisted of 6,595 consecutively treated men (median age: 68 years) with localized or locally advanced PC at the Chicago PC Center between 1997 and 2013. Fine and Gray competing risks regression analyses (table) were used to assess the risk of PCSM in men with favorable intermediate, unfavorable intermediate or high-risk compared to low-risk PC, adjusting for age at and year of treatment. Results: After median follow-up of 7.76 years, 820 men died: 72 of PC. While men with favorable intermediate-risk did not have significantly increased risk of PCSM as compared to low-risk PC (adjusted hazard ratio (HR) 1.28, 0.63-2.62 95% confidence interval (CI), p-value 0.49), men with high (adjusted HR 9.91, 5.48-17.94 95% CI, p-value <0.0001) or unfavorable intermediate-risk PC (adjusted HR 3.17, 1.60-6.30, p-value 0.001) did. Eight-year point estimates of PCSM were low: 0.68% [0.32-1.31% 95% CI] and 0.44% [0.25-0.75% 95% CI] for men with favorable intermediate and low-risk PC, respectively. Conclusions: Men with low and favorable intermediate-risk PC have similar and low estimates of PCSM during the first decade following standard management. These results provide evidence to support AS as an initial approach for men with favorable intermediate-risk PC. [Table: see text]

scholarly journals Effectiveness in Predicting the Response and Outcome with Three Prognostic Scoring Systems in Pediatric CML CP on Upfront Imatinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4549-4549
Author(s):  
Ganta Ranga Raman ◽  
Srividya Nasaka ◽  
Sadashivudu Gundeti ◽  
Vijay Gandhi Linga ◽  
Narendra Anukonda ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Scoring Systems ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Low Risk ◽  
P Value ◽  
Intermediate Risk ◽  
Hematological Response ◽  
Prognostic Scoring Systems

Abstract Introduction: The Sokal and Hasford (Euro) scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML).Recently, European Treatment and Outcome Study (EUTOS) scoring system was introduced. Data on risk stratification in pediatric CML population was lacking due to its rarity [<3%]. Objective: To study the effectiveness in predicting the response and outcome with three prognostic scores in pediatric CML-chronic phase patients on front line Imatinib. Materials and methods: We retrospectively analyzed the hospital records of newly diagnosed CML CP patients [aged ≤18 years] from 2004 to 2010 for their risk score, cytogenetic response and outcome at the end of 4 years. Outcome was measured in terms of event free survival (EFS) at the end of 48 months. Events include loss of hematological response, loss of cytological response, progression to accelerated/ blast phase (AP/BC). All received free Imatinib under Gleevac international patient assistance program. Results: Data of 106 children was analyzed with median age of 13.5 years [ranged 5-18 years] and male preponderance [M:F =1.14:1]. The distribution of children was 63%, 32% and 5% in Sokal low, intermediate and high risk respectively, 50%, 43% and 5% in Hasford/Euro low, intermediate and high risk respectively, 71% and 29% in EUTOS low and high risk respectively. The overall cumulative complete hematological response at the end of 3 month was 94%, and complete cytogenetic response at 18 months was 75%. The CCyR at 18 month was seen in 72%,76% and 100% among Sokal low, intermediate and high risk groups respectively, 74%, 73% and 100% among Hasford/Euro low, intermediate and high risk groups respectively, 81% and 86% EUTOS low and high risk groups respectively. The EFS at the end of 48 months was seen in 72%,64% and 83% among Sokal low, intermediate and high risk groups respectively; 70%, 63% and 83% among Hasford/Euro low, intermediate and high risk groups respectively; 73% and 66% EUTOS low and high risk groups respectively. Conclusion: None of the scoring systems predicted the response and outcome effectively in children with CML CP. Children with EUTOS low risk score had better EFS than high risk score but not statistically significant. These age group CML patients need to be studied and new prognostic scoring systems are needed to risk startify. Limitation of the study: small sample size, not a prospective study Table 1EventsEUTOS low risk n=76 (71%)EUTOS high risk n=30 (29%)p value (Fishers test)CHR at 3mon72/76 (94%)26/30 (86%)0.21CCyR at 12mon58/76 (76%)22/30 (73%)0.8CCyR at 18mon62/76 (81%)26/30 (86%)0.77EFS at 4 yrs56/76 (73%)20/30 (66%)0.48 Table 2 Events Sokal low risk n=66 (63%) Sokal intermediate risk n=34 (32%) Sokal high risk n=6 (5%) p value (Fishers test) CHR at 3mon 60/66 (100%) 34/34 (100%) 6/6 (100%) 0.18 CCyR at 12mon 32/66 (48%) 20/34 (58%) 5/6 (83%) 0.23 CCyR at 18mon 48/66 (72%) 26/34 (76%) 6/6 (100%) 0.4 EFS at 4 yrs 48/66 (72%) 22/34 (64%) 5/6 (83%) 0.6 Table 3 Events Euro low risk n=54 (50%) Euro intermediate risk n=46 (43%) Euro high risk n=6 (5%) p value (Fishers test) CHR at 3 mon 50/54 (92%) 46/46 (100%) 6/6 (100%) 0.16 CCyR at 12 mon 36/54 (66%) 26/46 (56%) 5/6 (83%) 0.36 CCyR at 18 mon 40/54 (74%) 34/46 (73%) 6/6 (100%) 0.46 EFS at 4 yrs 38/54 (70%) 30/46 (63%) 5/6 (83%) 0.94 Disclosures No relevant conflicts of interest to declare.

Evaluation of Integrated CLL Scoring System (ICSS) in 420 Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5563-5563 ◽  
Author(s):  
Andrea Visentin ◽  
Federica Frezzato ◽  
Silvia Imbergamo ◽  
Valentina Trimarco ◽  
Veronica Martini ◽  
...  
Keyword(s):  
High Risk ◽  
Predictive Accuracy ◽  
Lymphocytic Leukemia ◽  
Low Risk ◽  
Rank Test ◽  
High Risk Patients ◽  
Log Rank Test ◽  
Risk Patients ◽  
Normal Fish

Abstract BACKGROUND Chronic Lymphocytic Leukemia (CLL) is one of the most common hematological malignancies in Western countries. The disease is characterized by heterogeneous clinical course and outcome. During the last 15 years several clinical, biological and molecular prognostic factors have been identified, validated and some of them are currently used in patients' and treatment management. To improve the predictive accuracy of these markers, they have been combined into prognostic indexes (W. Wierda, JCO 2011, D. Rossi, Blood 2012, J. Bahlo, Haematologica 2015). Werecently proposed the Integrated CLL Scoring System (ICSS) based on cytogenetic abnormalities by FISH, IGHV mutational status and CD38 expression from 212 patients (A. Visentin et al, Clin Lymph Myeloma & Leuk 2015). The aim of this study was to validate the prognostic power of our index into a larger series of 420 CLL patients. METHODS 420 CLL patients referred to the Hematology Unit of Padua University Hospital from 1989 to 2015 were recruited in this study. According to ICSS, patients were classified as: low-risk, those patients with 13q deletion or normal FISH, IGVH mutated and CD38<30%; high-risk, subjects with 17p or 11q deletion and/or IGVH unmutated and CD38>30%; intermediate-risk, all remaining patients. Treatment free survival (TFS) was calculated as time from diagnosis to treatment (event), death or last known follow-up (censored). Overall survival (OS) was calculated from the date of diagnosis to death for any cause (event) or last known follow-up (censored). TFS and OS were compared with log-rank test and plotted using Kaplan-Meier method. The predictive accuracy of ICSS was evaluated by the Harrel's concordance index (c-index); a value >0.5 implies a good predictive ability. RESULTS The median age of our cohort was 62 years; 64% were male and 85% were Binet stage A at diagnosis. Cytogenetic analysis by FISH showed that 41 patients harbored 17p deletion, 50 11q deletion, 236 13q deletion, 44 trisomy 12 and 49 had normal FISH. 236 (56%) patients had IGHV gene homology >98% (i.e. mutated IGHV) and 103 (25%) expressed more then 30% of CD38. According to ICSS 202 (48%) subjects were classified as low-risk, 83 (20%) intermediate-risk and 135 (32%) high-risk. After a median follow-up of 81 months, the median TFS for ICSS classes of risk were 211, 70 and 27 months (log-rank test, p<0.0001, Figure 1A). The estimated 10-year TFS were 61%, 37% and 10% for low, intermediate and high-risk patients. The median OS were 213 and 136 months for intermediate and high-risk, while it was not reached for low-risk patients (Log-rank test, p<0.0001, Figure 1B). After 10 years from diagnosis the estimated OS were 88%, 79% and 57%, respectively. These data were confirmed by a multivariate analyses. In fact, high-risk patients had 5.3 and 4.0 times risk of start treatment and death than low-risk subjects, respectively (p<0.0001). This model was statistically internally validated, showing c-indexed of 0.712 and 0.693 for TFS and OS, respectively. In multivariate analyses, variables confirmed to predict adverse prognosis were male gender (p=0.0183), age>65years (p<0.0001), Rai III-IV (p=0.0025), Binet C (p=0.0002), 17p deletion (p=0.0002), TP53 abnormalities (p=0.0051), unmutated IGVH (p<0.0001), CD38>30% (p=0.0044) and high-risk ICSS (p<0.0001). CONCLUSIONS We herein provide evidence of the prognostic power and feasibility of ICSS into a large population of CLL patients. The use of this prognostic index could help physician into follow-up schedule, since high-risk patients should be monitored more often given the estimated increased risk of progression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Long-term outcomes of stereotactic body radiotherapy for low- and intermediate-risk prostate adenocarcinoma: A multi-institutional consortium study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 84-84 ◽  
Author(s):  
Amar Upadhyaya Kishan ◽  
Alan J. Katz ◽  
Constantine Mantz ◽  
Fang-I Chu ◽  
Limor Appelbaum ◽  
...  
Keyword(s):  
Risk Group ◽  
Survival Rates ◽  
Low Risk ◽  
Rank Test ◽  
Intermediate Risk ◽  
Long Term Outcomes ◽  
Log Rank Test ◽  
Gu Toxicity ◽  
Grade 3

84 Background: While a growing body of evidence supports the use of stereotactic body radiotherapy (SBRT) for the treatment of low- and intermediate-risk prostate adenocarcinoma (PCa), some trepidation exists regarding its long-term efficacy and safety. Methods: Men with low- and intermediate-risk PCa, as defined per the National Comprehensive Cancer Network guidelines, who were enrolled on various institutional phase II trials of SBRT between 2000-2012 were included in a multi-institutional consortium. Biochemical relapse (BCR) was defined as PSA > “nadir +2” or initiation of androgen deprivation therapy (ADT). Toxicity data were scored according to the CTCAE v 3.0 or Radiation Therapy Oncology Group scoring systems. Results: A total of 1644 men were eligible for analysis, with a median followup of 7.2 years. 297 patients (18.1%) had at least 9 years of followup. Fractionation schemes ranged from 33.50-40 Gy in 4-5 fractions. 892 patients had low-risk disease and 752 had intermediate-risk disease. 59 patients (3.6%) received short-term ADT. 100 patients (6.0%) experienced BCR, and 7 (0.4%) experienced distant metastases. No patients died of PCa. By Kaplan-Meier analysis, 5- and 10-year BCR-free survival rates were 98% and 94% in the low-risk group and 96% and 90% in the intermediate-risk group (p < 0.05 by log-rank test). 5- and 10-year overall survival rates were 93% and 86% in the low-risk group and 95% and 91% in the intermediate-risk group (p > 0.05 by log-rank test). Five patients (0.3%) experienced grade 3 acute genitourinary (GU) toxicities, including urinary retention, hematuria, and frequency. 30 (2%) experienced grade 3 late GU toxicity, including urinary strictures, hematuria, and retention. One late grade 4 GU toxicity (hemorrhagic urethritis) and one late grade 4 gastrointestinal toxicity (fistula-in-ano) were seen. Conclusions: To the best of our knowledge, this is the largest analysis of long-term outcomes following SBRT for PCa. The results indicate that SBRT has an efficacy and toxicity profile that compares favorably to more widespread forms of treatment, such as conventionally-fractionated external beam radiotherapy and brachytherapy.

scholarly journals Radiomics and MGMT promoter methylation for prognostication of newly diagnosed glioblastoma

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takahiro Sasaki ◽  
Manabu Kinoshita ◽  
Koji Fujita ◽  
Junya Fukai ◽  
Nobuhide Hayashi ◽  
...  
Keyword(s):  
High Risk ◽  
Predictive Accuracy ◽  
Risk Group ◽  
Prognostic Score ◽  
Methylation Status ◽  
Low Risk ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Log Rank Test ◽  
Newly Diagnosed Glioblastoma

Abstract We attempted to establish a magnetic resonance imaging (MRI)-based radiomic model for stratifying prognostic subgroups of newly diagnosed glioblastoma (GBM) patients and predicting O (6)-methylguanine-DNA methyltransferase promotor methylation (pMGMT-met) status of the tumor. Preoperative MRI scans from 201 newly diagnosed GBM patients were included in this study. A total of 489 texture features including the first-order feature, second-order features from 162 datasets, and location data from 182 datasets were collected. Supervised principal component analysis was used for prognostication and predictive modeling for pMGMT-met status was performed based on least absolute shrinkage and selection operator regression. 22 radiomic features that were correlated with prognosis were used to successfully stratify patients into high-risk and low-risk groups (p = 0.004, Log-rank test). The radiomic high- and low-risk stratification and pMGMT status were independent prognostic factors. As a matter of fact, predictive accuracy of the pMGMT methylation status was 67% when modeled by two significant radiomic features. A significant survival difference was observed among the combined high-risk group, combined intermediate-risk group (this group consists of radiomic low risk and pMGMT-unmet or radiomic high risk and pMGMT-met), and combined low-risk group (p = 0.0003, Log-rank test). Radiomics can be used to build a prognostic score for stratifying high- and low-risk GBM, which was an independent prognostic factor from pMGMT methylation status. On the other hand, predictive accuracy of the pMGMT methylation status by radiomic analysis was insufficient for practical use.

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