Prognostic factors versus markers of response to treatment versus surrogate endpoints: Three different concepts

2017 ◽  
Vol 23 (3) ◽  
pp. 378-381 ◽  
Author(s):  
Maria Pia Sormani
Keyword(s):  
Multiple Sclerosis ◽  
Prognostic Factors ◽  
Quantitative Assessment ◽  
Prognostic Markers ◽  
Response To Treatment ◽  
Surrogate Endpoints ◽  
Surrogate Markers ◽  
Methodological Issues ◽  
Baseline Factors

Multiple sclerosis is a highly heterogeneous disease; the quantitative assessment of disease progression is problematic for many reasons, including the lack of objective methods to measure disability and the long follow-up times needed to detect relevant and stable changes. For these reasons, the importance of prognostic markers, markers of response to treatments and of surrogate endpoints, is crucial in multiple sclerosis research. Aim of this report is to clarify some basic definitions and methodological issues about baseline factors to be considered prognostic markers or markers of response to treatment; to define the dynamic role that variables must have to be considered surrogate markers in relation to specific treatments.

scholarly journals Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis

2021 ◽  
Vol 11 (5) ◽  
pp. 335
Author(s):  
María José Zarzuelo Romero ◽  
Cristina Pérez Ramírez ◽  
María Isabel Carrasco Campos ◽  
Almudena Sánchez Martín ◽  
Miguel Ángel Calleja Hernández ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mechanism Of Action ◽  
Dimethyl Fumarate ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
New Therapies ◽  
Therapeutic Value ◽  
The Impact

The introduction of new therapies for the treatment of multiple sclerosis (MS) is a very recent phenomenon and little is known of their mechanism of action. Moreover, the response is subject to interindividual variability and may be affected by genetic factors, such as polymorphisms in the genes implicated in the pathologic environment, pharmacodynamics, and metabolism of the disease or in the mechanism of action of the medications, influencing the effectiveness of these therapies. This review evaluates the impact of pharmacogenetics on the response to treatment with new therapies in patients diagnosed with MS. The results suggest that polymorphisms detected in the GSTP1, ITGA4, NQO1, AKT1, and GP6 genes, for treatment with natalizumab, ZMIZ1, for fingolimod and dimethyl fumarate, ADA, for cladribine, and NOX3, for dimethyl fumarate, may be used in the future as predictive markers of treatment response to new therapies in MS patients. However, there are few existing studies and their samples are small, making it difficult to generalize the role of these genes in treatment with new therapies. Studies with larger sample sizes and longer follow-up are therefore needed to confirm the results of these studies.

Integrating Newer with Traditional Prognostic Factors in Evaluating Patients with CLL Receiving Frontline Chemoimmunotherapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2094-2094
Author(s):  
William G Wierda ◽  
Susan M O’Brien ◽  
Xuemei Wang ◽  
Stefan H Faderl ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Treatment Time ◽  
Rank Order ◽  
Leukemia Cell ◽  
Absolute Lymphocyte Count ◽  
Chromosome Abnormalities ◽  
Response To Treatment ◽  
Significant Prognostic Factor ◽  
Clinical Endpoint

Abstract Prognostic factors are important for evaluating patients (pts) with CLL, owing to heterogeneity in response to treatment and clinical course. The goal of this analysis was to evaluate the newer prognostic factors in relation to traditional ones in previously untreated pts receiving frontline chemoimmunotherapy. Traditional prognostic factors include age, Rai stage, absolute lymphocyte count (ALC), lymphocyte doubling time, and many others. Newer prognostic factors, include IgVH gene mutation status (MS), chromosome abnormalities by FISH, and leukemia cell expression of ZAP70. Finally, the clinical endpoint is important in considering and evaluating prognostic factors, since significant independent factors can be different for response to treatment, time to progression (TTP), and overall survival (OS). We evaluate 488 previously untreated pts who had an NCI-WG ‘96 indication for treatment and received frontline chemoimmunotherapy (CIT). Treatment was with a fludarabinebased CIT regimen: FCR (n=300), FCMR (n=30), FCR3 (n=65), FCR+GM-CSF (n=45), or CFAR (n=48). The CR rate, TTP, and OS were not significantly different between the CIT regimens; median follow-up times varied. The overall estimated median follow-up time was 62mo, TTP was 76mo, and OS was not reached. An extensive list of pretreatment characteristics were evaluated in univariable analyses as traditional factors including age, Rai stage, beta-2 microglobulin (β2M), CD38, and others, as well as newer prognostic factors including chromosome abnormalities by FISH, IgVH MS and ZAP70 expression by immunohistochemistry. Clinical endpoints included complete remission (CR), TTP, and OS. Multiple factors were significant (p<.05) and varied according to clinical endpoint. Next, we evaluated these significant factors in multivariable (MV) analyses to identify the significant (p<.05) independent factors for each endpoint. The rank order importance for each independent factor identified in the MV model with current follow-up is shown (Table 1). Table 1 Multivariable Model CR TTP OS We evaluated the newer prognostic factors (IgVH MS, del 17p, and ZAP70) separately in each final MV model to assess significant (p<.05) independent correlations (Table 2). # Pts in Model 483 301 483 # Events 351 101 106 Characteristic Rank-Order Significance in MV Model β2M 1 - 1 Hemoglobin 2 - - Age - 2 2 CD38 (30% cut point) - 3 - IgVH MS - 1 - Table 2 Significance of Factor in MV Model Characteristic CR TTP OS When including del 17p in models for TTP and OS, age and IgVH MS were no longer significant. Continued follow-up may identify additional important factors for time-toevent endpoints. Nomograms will be developed for each endpoint and full analyses will be shown. These analyses enable us to generate expectations and help in evaluating efficacy of new regimens for patients going on frontline CIT. Age, β2M, and del 17p appear to be the most important independent factors for OS in previously untreated patients who receive frontline CIT. Considering the newer prognostic factors, β2M continues to remain a major, independent, significant prognostic factor. Del 17p p<.05 p<.05 p<.05 IgVH MS Not Sig. p<.05 Not Sig. ZAP70 Not Sig. p<.05 p<.05

Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1992-1992 ◽  
Author(s):  
Eugen Tausch ◽  
Christina Galler ◽  
Richard Schlenk ◽  
Peter Hillmen ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Gene Mutations ◽  
Phase Iii ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Predictors of favorable response to implanted of ventriculoperitoneal shunt in patients with idiopathic normal pressure hydrocephalus

2020 ◽  
Vol 1 (1) ◽  
pp. 81-86
Author(s):  
Mario Emiliano Ricciardi ◽  
Ismael Calandri ◽  
Lucas Alessandro ◽  
Mauricio Farez ◽  
Juan Villalonga ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Retrospective Study ◽  
Normal Pressure Hydrocephalus ◽  
Ventriculoperitoneal Shunt ◽  
Normal Pressure ◽  
Idiopathic Normal Pressure Hydrocephalus ◽  
Response To Treatment ◽  
Clinical Factors ◽  
A Prospective Study

Introduction: The indication of a ventriculoperitoneal shunt (VPS) is discussed in patients with idiopathic normal pressure hydrocephalus (iNPH), due to the heterogeneity of the response to treatment and the risks involved in neurosurgery. Objective: To search for clinical factors and complementary studies in order to determine predictors of a favorable response to the VPS placement in patients with iNPH. Methodology: A retrospective study of patients with probable iNPH (according to international guidelines) treated with VPS assisted in a neurological clinic from January 2014 to January 2017 was conducted. A univariate statisticalanalysis of the variables considered as possible prognostic factors was performed. Results: 58 patients were included. Women presented 3.68 times more chances of improvement after the VPS (p=0.019). Good response to the gait test was associated with better response to the VPS (p=0.024). Conclusions: Female sex and good response to the gait test could be considered as predictors of a favorable response to the VPS placement in patients with iNPH. A prospective study is necessary to achieve a homogeneous diagnostic evaluation and a more extensive longitudinal follow-up to evaluate the clinical evolution in this group of patients.

scholarly journals Partial acute transverse myelitis is a predictor of multiple sclerosis in children

2014 ◽  
Vol 20 (11) ◽  
pp. 1485-1493 ◽  
Author(s):  
P Meyer ◽  
N Leboucq ◽  
N Molinari ◽  
A Roubertie ◽  
M Carneiro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Prognostic Factors ◽  
Severe Disease ◽  
Brain Mri ◽  
Age At Onset ◽  
Transverse Myelitis ◽  
First Episode ◽  
Acute Transverse Myelitis ◽  
Subsequent Risk

Background: Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis. Objectives: To determine the clinical course and prognostic factors after a first episode of ATM in children. Methods: Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected. Results: Median age at onset was 11 years (range 3–15 years). Follow-up data were available for a median of 4 years (range 0.5–16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3–11), with a 60% probability of having a relapse at five years ( p < 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%). Conclusion: Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.

scholarly journals NEP-Score Thresholds Predict Survival of Patients With Bronchial Carcinoids

2021 ◽  
Vol 11 ◽  
Author(s):  
Irene Gagliardi ◽  
Mario Tarquini ◽  
Maria Rosaria Ambrosio ◽  
Elisa Giannetta ◽  
Patricia Borges de Souza ◽  
...  
Keyword(s):  
Decision Making ◽  
Prognostic Factors ◽  
Therapeutic Strategy ◽  
Prognostic Markers ◽  
Prognostic Score ◽  
Therapeutic Strategies ◽  
Male Gender ◽  
Bronchial Carcinoids ◽  
Score Threshold

Survival prognostic markers are extremely needed to better define therapeutic strategies in patients with bronchial carcinoids (BC). We aim to verify the applicability of the NEP-Score in a homogeneous BC cohort and identify a derivative prognostic marker, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up. Sixty-four patients (38 females, and 26 males, mean age at diagnosis 58.9 ± 1.7 years) with BC were retrospectively evaluated. NEP-Score was calculated at the end of follow-up (NEP-T). A derivative score, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up, was then assessed. Patients were subdivided according to their living status at the end of follow-up. A NEP-Score threshold was investigated to predict survival. Mean NEP-T and mean NEP-D were significantly lower in live patients at end of follow-up. A NEP-T cut-off &gt;138 significantly predicts survival. Atypical BC relapsed more frequently than Typical BC. Male gender and previous malignancy were negative prognostic factors for survival. We confirmed NEP-Score applicability in BC and NEP-D utility, being the latter a simple, quick, and cheap prognostic score that can help clinicians in decision making. The identified NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy. In this context, a validation study is needed.

Radiologically isolated syndrome: targeting miRNAs as prognostic biomarkers

Epigenomics ◽  
2020 ◽  
Vol 12 (23) ◽  
pp. 2065-2076
Author(s):  
María Muñoz-San Martín ◽  
Sandra Torras ◽  
René Robles-Cedeño ◽  
Maria Buxó ◽  
Imma Gomez ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Prognostic Factors ◽  
Prognostic Biomarkers ◽  
Circulating Mirnas ◽  
Radiologically Isolated Syndrome ◽  
Definite Multiple Sclerosis ◽  
Clinically Definite Multiple Sclerosis ◽  
Specific Profile

Aim: Some clinical and biological characteristics have been described as prognostic factors for clinical conversion into clinically definite multiple sclerosis in radiologically isolated syndrome (RIS) population. The aim of this study was to assess signatures of circulating miRNAs in those patients according to their conversion status after 5 years of follow-up. Patients & methods: OpenArray plates assessing 216 miRNA candidates were run in 15 RIS patients, and their relative abundances were analyzed. Results: A specific profile of deregulated circulating miRNAs (miR-144-3p, miR-448 and miR-653-3p in cerebrospinal fluid and miR-142-3p, miR-338-3p, miR-363-3p, miR-374b-5p, miR-424-5p, miR-483-3p in plasma) differentiated individuals who remained as RIS after 5 years of follow-up. Conclusion: Circulating miRNAs might be used as prognostic biomarkers for RIS patients.

scholarly journals Evidence of disease control: a realistic concept beyond NEDA in the treatment of multiple sclerosis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 566 ◽  
Author(s):  
Ana C. Londoño ◽  
Carlos A. Mora
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Disease Control ◽  
Tissue Damage ◽  
Early Stage ◽  
Response To Treatment ◽  
Stage Of Disease

Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in the systematic follow-up of patients with multiple sclerosis (MS), its ability to accomplish detection of surreptitious activity of disease is limited, thus being unable to prevent patients from falling into a non-reversible progressive phase of disease. A protocol of evaluation based on the use of validated biomarkers that is conducted at an early stage of disease would permit the capture of abnormal neuroimmunological phenomena and lead towards intervention with modifying therapy before tissue damage has been reached.

scholarly journals FutureMS Cohort Profile: A Scottish Multi-Centre Inception Cohort Study of Relapsing-Remitting Multiple Sclerosis

2021 ◽  
Author(s):  
P.K.A. Kearns ◽  
S.J. Martin ◽  
J. Chang ◽  
R. Meijboom ◽  
E.N. York ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cohort Study ◽  
Disease Activity ◽  
Treatment Decision ◽  
Response To Treatment ◽  
Disease Heterogeneity ◽  
Predictive Tools ◽  
Treatment Decision Making ◽  
Relapsing Remitting

ABSTRACTMultiple Sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries the most common cause of progressive neurological disability in working age persons. However, there is significant between-subject heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate, or aggressive disease course is very limited. There is therefore a need for integrated predictive tools to inform individualised treatment decision making. FutureMS is a nationally-representative, prospective observation cohort study comprising 440 participants with a new diagnosis of relapsing remitting MS living in Scotland between May 2016 and March 2019. Established with the aim of addressing this need for individualised predictive tools, the cohort is designed to combine detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow up at year one is complete and longer-term follow up is planned, beginning at five years after first visit. The study aims to address the biology and determinants of disease heterogeneity in MS. Here we describe the cohort design and present a profile of the participants at baseline and one year of follow up.

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