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Valsecchi, Maria Grazia, Meenakshi Devidas, Ausiliatrice Lucenti, et al. "Evaluation of Minimal Residual Disease As a Surrogate Endpoint for Event Free Survival in Childhood B-Lineage Acute Lymphoblastic Leukemia." Blood 128, no. 22 (2016): 759. http://dx.doi.org/10.1182/blood.v128.22.759.759.
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Abstract Introduction The need to optimize clinical evaluation of new drugs stimulates researchers and regulatory bodies to consider novel endpoints that facilitate assessment of the efficacy of a new drug earlier in time than do traditional endpoints. To be a useful marker of efficacy, an early endpoint must be an accurate surrogate for the true clinical endpoint. Minimal residual disease (MRD) is a strong prognostic factor for Event Free Survival (EFS) in children with newly diagnosed acute lymphoblastic leukemia (ALL) and is used routinely to assess treatment response and stratify treatment intensity. However, it is not known whether or not early MRD response is an accurate surrogate endpoint for EFS in evaluating the efficacy of treatment interventions. This study addresses for the first time in childhood ALL the formal validation of surrogacy of MRD levels at the end of induction treatment by a meta-analytic approach on individual data from two large phase III trials with a randomized question on type of steroids in induction (dexamethasone 10mg/m2/day vs prednisone 60mg/m2/day). Material and Methods We performed a meta-analysis of individual data of 2955 B-ALL patients from AIEOP-BFM-ALL2000 (NCT00613457, NCT00430118), and 945 and 930 high risk B-ALL patients randomized for steroids after being allocated either to Capizzi or High-dose Methotrexate in COG AALL0232 (NCT00075725; separately considered due to the significant quantitative interaction between Methotrexate regimens and type of steroid). The trials included evaluation of MRD at day +33 (PCR-MRD) and +29 (flow-cytometry MRD), respectively, with a sensitivity of at least 10-4. The three categories MRD level (negative, low positive i.e. <5x10-4 and positive ≥5x10-4), was assessed as surrogate for the EFS endpoint (time to event defined as resistance at the end of induction, relapse, death in remission, second malignancy). A two-level modelling approach was used to estimate the association between MRD and EFS and between the treatment effect on MRD (proportional odds model) and on EFS (proportional hazard model). The quality of the surrogate at the individual level was assessed on the basis of the bivariate Plackett copula model, with a parameter representing the global odds ratio. The quality of the surrogate at the trial level was assessed on the basis of the coefficient of determination R2trial from a linear regression through the estimated treatment effects. Results The main results on MRD and EFS by trial and treatment are in table 1. The meta-analytic approach shows that MRD at the end of induction is a poor surrogate for treatment effect on EFS (Figure 1) at the trial level, with R2trial=0.09 (95% CI: 0-0.29), while, at the individual level, it shows a considerable prognostic association with EFS, after adjusting for treatment, with a 3.9 odds ratio of failure for patients with higher compared to lower MRD levels (95% CI: 3.4-4.4). Additional sensitivity analyses on relevant subgroups generally confirmed the previous findings both at the trial and patient level association. Conclusions Using a meta-analytic approach, we found that MRD, in 3 categories defined according to standard cut-points, is a poor surrogate for EFS at the trial level, thus indicating that the effect of the randomized steroids (dexamethasone vs. prednisone in induction) on the MRD level at the end of induction does not reliably predict the effect of the intervention on EFS. In contrast, the analysis shows a strong and highly significant association between end induction MRD level and EFS time for individual patients, regardless of treatment, confirming the prognostic effect of early MRD response on clinical outcome. This study shows, for the first time, the limitation of a strong prognostic factor in being a surrogate in the context of front line ALL treatments. The impact of type of steroid on MRD distribution at the end of induction is relatively limited and subsequent treatment complexity and intensity, partly tailored on MRD itself as a key criterion used to modulate the intensity of post-induction therapy, may dilute a potential surrogacy. These data suggest that clinicians and regulatory bodies should be cautious in using early MRD response in the context of complex multiagent therapy as an early surrogate endpoint to evaluate the effect of a randomized treatment intervention on long-term EFS. Disclosures Moricke: JazzPharma: Honoraria, Other: financial support of travel costs. Biondi:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; BMS: Membership on an entity's Board of Directors or advisory committees; Cellgene: Other: Advisory Board.
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Hjelmgren, Jonas, Kristoffer Nilsson, and Gunnar Birgegård. "JAK2 V617F as a Marker for Long-Term Disease Progression and Mortality in Polycythemia Vera and its Role in Economic Modeling." Journal of Health Economics and Outcomes Research 7, no. 1 (2020): 61–70. http://dx.doi.org/10.36469/jheor.2020.13083.
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Background: In order to facilitate sound economic evaluations of novel treatments, health-economic models of polycythemia vera (PV) must combine effects on surrogate endpoints in trials with disease progression (DP) and mortality in long-term cohort data. Objective: We validate an economic model for PV that uses Janus Kinase 2 (JAK2) burden as a surrogate endpoint to predict DP (thrombosis, myelofibrosis, and acute leukemia) and overall survival (OS) based on progression-specific mortality. Methods: Long-term observational studies that include information about baseline JAK2 burden were identified via PubMed searches and used to validate the model. Kaplan-Meier (KM) OS curves were extracted using a digitizing software. External validity of the model was analyzed by visually comparing OS curves of the model with the KM curves of the included studies, as well as calculating differences in mean OS estimated as area under the curve (AUC). Results: The model’s predictions of cumulative DP were somewhat lower than the published studies. Over 20 years’ time, our base case model predicted a mean OS for a PV patient (15.0–16.5 years), which was in line with the published studies (15.8–17.5 years). Modeled mean OS was almost two years longer (1.6–1.9 years) for patients with JAK2 <50% than patients with JAK2 ≥50%. Only three long-term observational studies that satisfied the predefined criteria were found and could be used in the validation, but these studies did not capture JAK2 evolution over time. Improved model predictions of DP and mortality based on the longitudinal evolution of JAK2 could be derived from real-world data sources. Such data are currently scarce and future observational studies should be designed to capture the long-term impact of JAK2 on DP and mortality in PV.
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Yin, Jun, Geoffrey L. Uy, Betsy Laplant, et al. "Event-Free Survival As a Surrogate Endpoint for Overall Survival in Previously Untreated Acute Myeloid Leukemia: An Individual Patient-Level Analysis of Multiple Randomized Trials (Alliance A151614)." Blood 132, Supplement 1 (2018): 1386. http://dx.doi.org/10.1182/blood-2018-99-113902.
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Abstract Background: Overall survival (OS) remains the definitive primary efficacy endpoint to evaluate previously untreated acute myeloid leukemia (AML) therapies, but it requires prolonged follow-up. An earlier endpoint assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate event-free survival (EFS) as a surrogate endpoint for OS in untreated AML. Methods: Individual patient data were analyzed from 2,475 patients (pts) from 4 multicenter, randomized controlled phase III trials of active treatment in previously untreated AML using anthracycline and cytarabine induction chemotherapy as the concurrent control (CALGB 10201, n=506, enrollment period 2003-2006, age 60-88 years (y); CALGB 10603, n=717, enrollment period 2008-2015, age 18-60 y, FLT3-mutated pts only; SWOG 0106, n=595, enrollment period 2004-2009, age 18-60 y; ECOG-ACRIN 1900, n=657, enrollment period 2002-2008, age 17-60 y). Individual patient-level surrogacy examines the association between the individual patients' EFS and OS time after adjusting for treatment effect, and was assessed using the copula bivariate survival model (Kendall's tau). Trial-level surrogacy measures how precisely the treatment effect on OS can be predicted on the basis of observed treatment effect on EFS, and was evaluated using both linear regression (R2WLS) weighted by trial size and Copula bivariate (R2Copula) models. Pre-specified criteria for surrogacy required either R2WLS or R2Copula ≥0.80, neither below 0.7, with either lower bound 95% Confidence Interval (CI) >0.60. Sensitivity analyses were conducted using different EFS definitions (Table 1). Results: With a median follow-up of 50.2 months for the 896 patients still alive, the median OS and EFS across all four trials were 20.9 months (95% CI: 19.0-22.7) and 5.6 months (95% CI: 4.5-6.4), respectively. Trial-level surrogacy for EFS was strong (R2WLS=0.79; R2Copula=0.89), indicating a high correlation of treatment effect between EFS and OS. At the individual patient-level, however, EFS showed weak association with OS (tau= 0.52), compared to the strength of trial-level surrogacy. The discrepancy between patient-level EFS and OS was greatest among patients who did not achieve a CR, followed by those who achieved a CR but relapsed (Figure 1). Sensitivity analysis on alternative EFS definitions showed that the trial-level surrogacy was similar, but individual patient-level surrogacy varied across different EFS definitions (Table 1). This is consistent with what we previously reported (ASH 2016): EFS estimates differed considerably based on the definition of induction failure (IF) in a single arm setting, but this had minimal impact on the estimation of the treatment effect using EFS in randomized trials. In addition, when considering only relapse and death as events (definition 4), both individual patient- and trial-level correlations were high. Conclusions: Correlation between EFS and OS was impacted by patients not achieving CR during induction. Despite the lack of patient-level correlation, a strong correlation between hazard ratios for treatment effects was observed between EFS and OS on the trial level. Hence, it remains debatable whether EFS represents a clinical benefit in itself for patient with untreated AML considering the strong correlation in treatment effects. Further validation is needed due to the small number of trials included and the heterogeneity across trials. Acknowledgment: We gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf, SWOG S0106 Study Chair. Support: U10CA180821, U10CA180882, U10CA180794, U10CA180820, U10CA180888; Clinicaltrials.gov Identifiers: NCT00085124 (10201), NCT00651261 (10603), NCT01253070 (11001), NCT00085709 (SWOG S0106), and NCT00049517 (ECOG-ACRIN E1900) Disclosures Uy: Curis: Consultancy; GlycoMimetics: Consultancy. Larson:Pfizer: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding.
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Schilhabel, Anke, Henrik Knecht, Anton W. Langerak, et al. "Analytical Validation of Patient-Specific PCR-Based MRD Assessment for Use As a Primary Endpoint in CLL Clinical Trials." Blood 126, no. 23 (2015): 2924. http://dx.doi.org/10.1182/blood.v126.23.2924.2924.
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Abstract Introduction. Minimal residual disease (MRD) is an objective measure of disease status defined by the number of leukemic cells in the blood or bone marrow of leukemic patients. In recent clinical studies of chronic lymphocytic leukemia (CLL), undetectable MRD levels (< 1 tumor cell/10,000 leukocytes) have been shown to correlate with prolonged progression free survival (PFS) and overall survival, independent of treatment or known risk factors. MRD assessment has been proposed as an alternative to PFS as a primary endpoint in frontline CLL pivotal studies to evaluate the efficacy of novel therapies at an earlier time-point. Thorough standardization and validation are needed to use MRD as a primary surrogate endpoint. Allele specific oligonucleotide (ASO)-PCR of immunoglobulin (IG) gene rearrangements is a method for quantifying MRD using patient-specific PCR primers and has been standardized by the EuroMRD Consortium (www.EuroMRD.org). Given that each patient has individualized PCR primers designed for their leukemic clone, this posed a unique challenge for the analytical validation studies to demonstrate that the assays are uniform in their reproducibility and analytical sensitivity to measure MRD across patients with CLL. Here we report a comprehensive, IVD-guided analytical validation of the ASO-PCR technique according to the guidance of regulatory authorities. We provide evidence that the ASO-PCR methodology can reproducibly measure MRD to the required threshold of 10-4, across patients with CLL. Results. Performance of ASO-PCR was assessed using a combination of retrospective data from the CLL11 clinical trial and prospectively performed experiments. Patient assays from 60 CLL patients were tested in two EuroMRD laboratories to demonstrate linearity across the measurement range of 10-1 to 10-5, and a limit of detection of 6.3x10-5, which is below the cut-off of 10-4 used for defining MRD negativity. Concordance of the method to an orthogonal method was determined from the previously published comparison of flow cytometry with ASO-PCR (Boettcher et al., Leukemia 2009; 23: 2007) with 93.8 % overall agreement between both methods (n=452). Agreement of MRD status was >97% when comparing individually designed ASO primers for the same patient within the lab. The overall agreement between the two different laboratories using independently designed ASO-PCR assays was 93.5%. Precision was assessed above and below the threshold of 10-4 using ASO-PCR assays of 3 individual patient samples diluted to appropriate MRD levels listed in Table 1. Theexperiment was designed to mimic sources of variation by evaluating MRD samples over the course of the clinical study (3 days x 2 operators x 3 patients x 2 laboratories x 3 replicates). Overall variability was estimated using a mixed effects model including fixed patient effects and random effects for operator and day. Based on the known MRD distribution of frontline CLL patients, we estimate acceptable overall variability on the order of 80% CV at lower concentrations (≤ 3.2x10-4) and 40% CV at higher concentrations (> 3.2x10-4). This precision estimate provides reasonable misclassification rates (< 5%) due to the fact that the majority of patients had MRD levels either well above or below 10-4 level. Experiments also addressed stability of patient specimens and critical assay components. Table 1. Precision of ASO-PCR results obtained at MRD levels 10-2 to 10-5Table 1.Estimated Total CV (%) Averaged Across 3 patientsMRD levelKielErasmus1.00E-028.7034.791.00E-0310.0235.743.20E-0415.8233.271.00E-0431.7036.383.20E-0589.8978.801.00E-05258.06277.27 Conclusion. The analytical validation studies described here provide evidence that the ASO-PCR methodology, standardized by EuroMRD, performs well to reproducibly detect MRD status across CLL patients at the threshold of 10-4. These studies serve as an example for the validation of personalized, patient-specific quantitative clinical assays for use as a primary endpoint in clinical trials. The authors would like to acknowledge the valuable work of the following people who contributed to this work: M. Brüggemann (UKSH Kiel), R Raja, C. Cox, W. Darbonne, R. Desai, and K. Trunzer. Disclosures Langerak: DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics.; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). van Dongen:BD Biosciences (cont'd): Other: Laboratory Services in the field of technical validation of EuroFlow-OneFlow antibody tubes in dried format. The Laboratory Services are provided by the Laboratory of Medical Immunology, Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of IP on Infinicyt software, Patents on EuroFlow-based flowcytometric Diagnosis and Classification of hematological malignancies, Patents on MRD diagnostics, and Patents on PID diagnostics.; Cytognos (continued): Patents & Royalties: Royalty income for EuroFlow Consortium. The Infinicyt software is provided to all EuroFlow members free-of-charge.Licensing of Patent on detection of IgE+ B-cells in allergic diseases. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics.. Royalty income for EuroClonality-BIOMED-2 Consortium; Immunostep: Patents & Royalties: Licensing of IP and Patents on immunobead-based dection of fusion proteins in acute leukemias and other tumors. Royalties for Dept. of Immunology, Erasmus MC and for EuroFlow Consortium; BD Biosciences: Other: Educational Services: Educational Lectures and Educational Workshops (+ related travelling costs). The lectures and workshops fully focus on the scientific achievements of the EuroFlow Consortium (No advertisement of products of BD Biosciences)., Patents & Royalties: Licensing of IP and Patent on EuroFlow-based flowcytometric Diagnosis and Classification of hematological malignancies; Royalty income for EuroFlow Consortium.; Roche: Consultancy, Other: Laboratory Services in the field of MRD diagnostics, provided by the Laboratory of Medical Immunology, Dept. of Immunology, Erasmus MC, Rotterdam, NL.. Ray:Genentech, Inc.: Employment. Punnoose:Genentech, Inc.: Employment. Kim:Genentech, Inc.: Employment. Haberberger:Genentech, Inc.: Employment. Bernaards:Roche: Employment. Zhu:Genentech, Inc.: Employment. Lewin-Koh:Genentech, Inc.: Employment. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Dimier, Natalie, Paul Delmar, Carol Ward, et al. "A Model for Predicting Effect of Treatment on Progression-Free Survival Using Minimal Residual Disease As a Surrogate Endpoint in Chronic Lymphocytic Leukemia." Blood 126, no. 23 (2015): 720. http://dx.doi.org/10.1182/blood.v126.23.720.720.
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Abstract Introduction The standard primary endpoint in clinical trials of chronic lymphocytic leukemia (CLL) is progression-free survival (PFS). Given the increasingly long follow up required to detect differences in PFS between treatment arms in the era of more efficient therapeutics, valid surrogate endpoints are urgently needed to reduce clinical trial duration, thereby accelerating drug development, reducing costs and allowing patients (pts) earlier access to novel treatment options. Pts with CLL who achieve levels of minimal residual disease (MRD) of <1 clonal cell/10.000 leukocytes in peripheral blood (PB) as determined by multicolor flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) at the end of initial treatment are considered MRD negative, and have been shown to experience significantly improved PFS. This analysis aimed to support the evaluation of MRD response at the end of treatment as a surrogate endpoint for PFS in CLL, based on a retrospective analysis of 3 multicenter, randomized, Phase 3 clinical trials. Methods MRD was prospectively assessed in PB of treatment-naive pts with CLL that participated in the German CLL Study Group CLL8, CLL10 and CLL11 multicenter, randomized, open-label, Phase 3 clinical trials, which included induction treatment followed by observation. The primary endpoint of each study was investigator-assessed PFS. MRD was quantified by 4-color flow cytometry in CLL8 and CLL10, and ASO RQ-PCR in CLL11. Both methods had a detection threshold of 1 CLL cell/10,000 leukocytes. Pts who had no MRD result but had disease progression or died shortly after 6 treatment cycles (within 90 [CLL8 and CLL10] or 56 [CLL11] days of last dose) were included and classed as MRD positive. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on MRD. Log ratio was selected as the most reliable representation of MRD response based on the best model fit. To ensure no systemic bias with pt selection, demographic characteristics and efficacy results for the pt population used in the MRD analysis were compared with the respective intent-to-treat populations for each study. Results PB MRD levels at the end of treatment (CLL8 and CLL10, 75-195 days after last dose; CLL11, 56-190 days after last dose) were assessed in 393, 336, and 474 pts from CLL8, CLL10 and CLL11, respectively. PFS events occurred in 24% to 51% of pts assessed for MRD assigned to the experimental arm and in 34% to 67% assigned to active control treatment. Key efficacy data for the 3 trials are shown in Table 1. To fit a meta-regression model, each study was split into subgroups according to region (CLL8), country (CLL11) or randomly (CLL10). For each subgroup, the PFS hazard ratio (HR) was plotted against the ratio of MRD response rates (MRD negative rate in experimental arm to MRD negative rate in control arm, on a log-scale), and a regression line fitted to reflect the relationship between the two parameters (Figure 1). Circle size represents the weighting of each subgroup to the overall model; least variability in PFS HR have the largest circles. Clustering of circles by study reflects the overall treatment effect (for both MRD and PFS) in the studies. A statistically significant relationship between improved MRD response rates and reduction in the risk of disease progression or death was observed (for each unit increase in log of the ratio of MRD response rates, the log of PFS HR decreases by -0.299; 95% CI, -0.441 to -0.157; p=0.0004). Predictions based on this meta-regression model suggest that risk of progression or death decreases as the ratio of MRD response rates (MRD relative risk: MRD-negative rate in experimental arm/MRD-negative rate in control arm) increases (Table 2); i.e. a larger difference in MRD-response rates leads to lower PFS HR. Conclusion A surrogate endpoint (MRD) should not only provide prognostic value for the specific clinical outcome (PFS), but also evidence that treatment effect on the surrogate endpoint (MRD) reliably predicts treatment effect on the clinical outcome (PFS). Results of the meta-regression model show a significant association between treatment effect on MRD and treatment effect on PFS with regard to chemoimmunotherapy. The findings also suggest that treatment effect on PFS can be predicted based on treatment effect on MRD response. This model supports the use of MRD as a surrogate for PFS in pts with CLL. Disclosures Dimier: Roche: Employment. Delmar:F. Hoffmann-La Roche, Ltd.: Employment, Equity Ownership. Ward:F. Hoffmann-La Roche Ltd: Employment. Morariu-Zamfir:F. Hoffmann-La Roche Ltd: Employment. Fingerle-Rowson:Roche: Employment, Equity Ownership. Fischer:Roche: Other: Travel Grants. Eichhorst:Mundipharma: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau. Goede:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; GSK: Honoraria; Bristol-Myers Squibb: Honoraria. van Dongen:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. Royalty income for EuroClonality-BIOMED-2 Consortium.; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of Patent on detection of IgE+ B-cells in allergic diseases. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Cytognos: Patents & Royalties: Licensing of IP on Infinicyt software, Patents on EuroFlow-based flowcytometric Diagnosis and Classification of hematological malignancies, Patents on MRD diagnostics, and Patents on PID diagnostics. Royalty income for EuroFlow Consortium.; BD Biosciences: Other: Educational Lectures and Educational Workshops (+ related travelling costs). Laboratory Services in the field of technical validation of EuroFlow-OneFlow antibody tubes in dried format. Provided by the Laboratory of Medical Immunology, Erasums MC, Patents & Royalties; Roche: Consultancy, Other: Laboratory Services in the field of MRD diagnostics, provided by the Laboratory of Medical Immunology, Dept. of Immunology, Erasmus MC, Rotterdam, NL; Immunostep: Patents & Royalties: Licensing of IP and Patents on immunobead-based dection of fusion proteins in acute leukemias and other tumors. Royalties for Dept. of Immunology, Erasmus MC and for EuroFlow Consortium. Ritgen:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Böttcher:Celgene: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Beckton Dickinson: Honoraria. Langerak:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics. ; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding.
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Wang, Xiaofei, Xiaoyi Wang, Lydia Hodgson, et al. "Validation of Progression‐Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials." Oncologist 22, no. 2 (2017): 189–98. http://dx.doi.org/10.1634/theoncologist.2016-0121.
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Kaur, Pavinder, Anil Pahuja, Kevin Nguyen, et al. "Best Practices for Validation of Measurable Residual Disease Assessments By Multiparameter Flow Cytometry in Emerging Clinical Trials of Acute Myeloid Leukemia." Blood 136, Supplement 1 (2020): 22–23. http://dx.doi.org/10.1182/blood-2020-137787.
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Background: Measurable Residual Disease (MRD) assessments are gaining increasing acceptance as a prognostic factor for tailoring treatment in hematological malignancies. Acute Myeloid Leukemia (AML) is a heterogeneous disease with high relapse rates and presents a high unmet need for effective treatment options. Measurement of residual disease after therapy reflects a combination of all resistance mechanisms and is currently used for guiding treatment options. Study Design: In this study, we aimed to validate an AML-MRD assay by multiparameter flow cytometry (MFC) methodology. This is a 4-tube, 8-parameter assay designed to incorporate cell differentiation (CD) markers for identification of a diverse group (covering roughly 90% of patients, Cloos et al, 2018) of Leukemia Associated Immunophenotypes (LAIPs) to accurately identify both native phenotypes and phenotype shifts after drug treatment. These CD markers were selected based on extensive investigation of many markers and in line with the consensus recommendations from European Leukemia Network AML working party (Schuurhuis et al, 2018), while specimen testing and interpretation principles were performed in accordance with Cloos et al, 2018. The assay validation focused on evaluation of sensitivity (MRD cut point and LOD), precision and accuracy as key criteria for evaluating assay performance utilizing primary patient specimens and AML cell lines representing different LAIPs. The results were orthogonally verified in a blinded manner by morphologic assessment at Navigate and by the MRD-team at VUMC Amsterdam. Results: Two experimental approaches were adopted to evaluate analytical and functional sensitivity (clinical applicability) of the assay. Results indicated analytical sensitivity (LOD) as low as 0.01% LAIPs of total WBC and functional sensitivity (LOQ) of 0.1% (MRD cut point). Excellent repeatability and reproducibility (less than 20% CV) was observed across instruments, operators and independent measurements (n = 75). The frequencies of AML blasts detected by MFC and morphological examination were highly concordant (Spearman r = 0.95, P value &lt; 0.001, n = 24). LAIPs deduced across nine patient specimens by the Navigate laboratory were independently confirmed by the MRD-team at VUMC Amsterdam. Conclusion: In summary, based on the use of consensus markers recommended by ELN for reliable capture of a broad group of LAIPs in AML patients and verification of key assay performance characteristics, we believe this comprehensive MFC based AML MRD assay is fit-for-purpose for accurately assessing measurable residual disease. Following clinical trial validation, MRD might be used as a surrogate endpoint for approval of emerging agents. Disclosures Marques Ramos: Novartis: Current Employment. Larson:BMS, Bioline, Celgene, Juno, Janssen: Research Funding; TORL Biotherapeutics: Current equity holder in private company. Sarikonda:Novartis: Current Employment.
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Xie, Zhiyi, Lisa Chamberlain, Andrew Carson, et al. "Monitoring Minimal Residual Disease in Acute Myeloid Leukemia Using Genomic or cfDNA with MyMRD®, a Targeted NGS Panel." Blood 132, Supplement 1 (2018): 5268. http://dx.doi.org/10.1182/blood-2018-99-118971.
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Abstract Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous disorder. Precision therapies for AML have been developed that target specific driver mutations. The efficacies of these therapies are variable, making it critical to determine successful therapies prior to patient relapse. For patients achieving a first complete remission, minimum residual disease (MRD) is an important prognostic factor, as MRD may provide a powerful and timely tool to evaluate therapeutic efficacy. There is a growing demand that new and promising drugs are approved as quickly as possible and accelerated approvals will require biomarker surrogate endpoints, such as MRD, rather than long-term survival endpoints. We have developed a sensitive NGS gene panel (MyMRD®), which identifies pathogenic variants in AML. The MyMRD panel targets single nucleotide variants (SNVs), insertions and deletions (indels) in coding exons of hotspots of 21 genes (ASXL1 BRAF CALR CEBPA CSF3R DNMT3A FLT3 IDH1 IDH2 JAK2 KIT KRAS MPL NPM1 NRAS PTPN11 RUNX1 SF3B1 SRSF2 TP53 ZRSR2), and structural variants of potential genomic breakpoint hotspots within 3 somatic gene fusion partners (CBFB-MYH11 KMT2A RUNX1-RUNX1T1). This 23 gene targeted panel can identify driver mutations that cause relapse in >90% of all AML patients, as well as common drivers in other myeloid neoplasms and myelodysplasic syndromes. MyMRD panel validation included determining the limit of blank (LoB), limit of detection (LoD), and linearity. Validation samples were generated using known variant containing DNA from cell lines and clinical samples diluted into NA12878 ("Genome in a Bottle") DNA. The average background, crossover, and carryover rates were determined to be 0.017%, 0.023%, and 0.016%, respectively. The LoB was determined to be 0.13% from calculating each of expected variants using the 95th percentile of all negative samples. Overall, we established an LoD of 0.5% for >95% of the targeted SNV and indel sites in the assay with lower LoDs for specific mutations of interest, such as 0.17% for FLT3 TKD and 0.34% for NPM1. The LoD for structure variants was determined to be 1.8%. The assay shows strong linearity with R2 = 0.969 - 0.994 of 11 selected targets in the entire range (0.17% - 50%) of variant allele frequencies (VAFs) tested. Linearity and LoD determined from clinical samples containing SNVs and indels were consistent with conclusions obtained from contrived cell line samples. Cell-free DNA (cfDNA) isolated from plasma is becoming a readily available source ofcirculating tumor DNA for testing. A similar molecular profile has been observed from cfDNA to that of bone-marrow tumor cells from multiple myeloma patients. Therefore, we investigated whether the MyMRD assay, developed for genomic DNA analysis, could be applied to cfDNA to assess variants at a level comparable to testing of genomic DNA. To overcome the limitation of cfDNA availability, DNA fragments with size similar to cfDNA (140-170bp), were generated from contrived cell line DNA to assess the LoD and linearity of assay. The cfDNA assay also showed strong linearity (R2=0.975 - 0.998) in the range of VAFs (0.1- 20%) tested. With cfDNA input of 25ng, the LoD was established to be 0.5% for targeted SNV sites, and 1% for targeted indel sites. The MyMRD cfDNA assay detected variants at the same LoD for SNVs and a slightly higher LoD for indels. Additional clinical samples were tested with the MyMRD assay. Variants detected were verified with capillary electrophoresis and/or amplicon-based NGS assays. The results showed 100% concordance with the MyMRD panel assay. The MyMRD gene panel is a sensitive and reliable assay that provides monitoring of MRD using genomic DNA and cfDNA. The assay is shown to detect clinically important driver variants and to have excellent linearity and LoD for targeted sites. The assay provides an accurate method for detecting mutations in multiple targets in patients and can be used to stratify patients for therapy and clinical trials, and may provide the sensitivity necessary to serve as a surrogate endpoint assay for targeted therapies in AML. Disclosures Xie: Invivoscribe Inc.: Employment. Chamberlain:Invivoscribe Inc.: Employment. Carson:Invivoscribe Inc.: Employment. Atkinson:Invivoscribe Inc.: Employment. McClain:Invivoscribe Inc.: Employment. Sprague:Invivoscribe, Inc.: Employment. Kiya:Invivoscribe Inc.: Employment. Xia:Invivoscribe Inc.: Employment. Huang:Invivoscribe Inc.: Employment. Patay:Invivoscribe Inc.: Consultancy, Equity Ownership, Patents & Royalties. Blankfard:Invivoscribe Inc.: Employment. Miller:Invivoscribe, Inc.: Employment, Equity Ownership.
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Catania, Gioacchino, Federico Monaco, Massimo Pini, et al. "Prognostic Impact of p190 and p210 Co-Expression at Diagnosis in Chronic Myeloid Leukemia (CML) Patients Treated with Imatinib." Blood 124, no. 21 (2014): 5528. http://dx.doi.org/10.1182/blood.v124.21.5528.5528.
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Abstract Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing1. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability. Aim: Primary object of this study was to investigate if the co-expression might influence the rate of early outcome surrogate endpoints such as such as early complete cytogenetic response in patients treated with imatinib. The secondary endpoint was the evaluation of failure free survival (FFS) measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase, death for any cause and switch to nilotinib/dasatinib for resistance or intolerance. Methods: Were evaluated patients with CML in chronic phase treated with imatinib at our institution. We excluded cases with less than one year of treatment and/or treated with other TKIs or conventional chemotherapy.The fusion transcripts BCR-ABL were evaluated at diagnosis in peripheral blood by NESTED-PCR2 and the cytogenetic response were evaluated in bone marrow cells with G-banding technique and fluorescent in situ hybridization (FISH)3. The patients were divided into two groups, "double transcripts" (DT) and "single transcript" (ST). All patients received imatinib 400 mg/die. Results: A total of 56 patients were analyzed. The median age of patients was 58 years (range 28-80 years) and 35 (62%) were male. Twenty patients (36%) were DT and thirty-six (64 %) ST. The distribution according to Sokal score was: 7 (35%), 8 (40%) and 5 (25%) patients for low, intermediate and high risk in the DT, whereas 18 (50%), 15 (42%) and 3 (8%) low, intermediate and high risk in ST, respectively. The complete cytogenetic response at 3 months was achieved in 2 patients with DT and 7 patients with ST (10% vs 19% p 0.35), at 6-month complete cytogenetic response was achieved in 8 patients with DT and 27 patients with ST (40% vs 75% p 0.01) (Table 1). After median follow-up of 1966 days, the FFS was significantly different between the DT and ST (55% vs 5 % p< 0.001) (figure 1), 11 patients in the DT group and 5 patients in ST group had shift to TKI 2¡ generation (55% vs 14% p 0.001) and 4 patients in DT group not achieved complete cytogenetic response. Summary/Conclusion: In our study the co-expression of p190 and p210 BCR-ABL transcripts influences the early cytogenetic response to imatinib and suggesting the need for a larger validation study Reference 1). van Rhee F, Hochhaus A, Lin F, Melo JV, Goldman JM, Cross NC. : "p190 BCR-ABL mRNA is expressed at low levels in p210-positive chronic myeloid and acute lymphoblastic leukemias."Blood. 1996 15;87:5213-7. 2). Hermans A, Selleri L, Gow J, Wiedemann L, Grosveld G: "Molecular analysis of the Philadelphia translocation in chronic myelocytic and acute lymphocytic leukemia." Leukemia 2:628,1988. 3) Landstrom AP, Tefferi A.: "Fluorescent in situ hybridization in the diagnosis, prognosis, and treatment monitoring of chronic myeloid leukaemia".Leuk Lymphoma.2006;47:397-402. Figure 1: Failure Free Survival: Figure 1:. Failure Free Survival: Table 1 : Complete Cytogenetic response: Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
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Malek, Sami N., Peter Ouillette, Harry Erba, et al. "Genomic Complexity Identifies Patients with Agressive Chronic Lymphocytic Leukemia." Blood 110, no. 11 (2007): 489. http://dx.doi.org/10.1182/blood.v110.11.489.489.
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Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. CLL has a varied clinical course. Risk assessment and patient counseling relies on clinical parameters and validated biomarkers. Genetic biomarkers, as exemplified in the CLL FISH panel, allow for CLL patient risk stratification. Nonetheless, a subset of patients with apparently favorable lesions (del13q14 or normal FISH results) progresses rapidly and a fraction of patients with unfavorable findings (del17p or del11q) progress at less than predicted rate. Method: We studied 117 previously untreated CLL patients enrolled into a prospective study at the University of Michigan. We obtained unbiased, high-density, genome-wide measurements of sub-chromosomal copy number changes in highly purified DNA from sorted CD19+ cells and buccal cells using the Affymetrix 50K SNP-array platform. A genomic complexity score was derived and correlated with the validated surrogate endpoint time to first therapy (TTFT), a measure of disease aggressiveness. Genomic complexity was measured using two complementary methods: i) visual inspection of dChipSNP-generated heatmap displays for copy-number estimates for all patients and for all chromosomes. Two of the authors independently reviewed dChipSNP-based copy number displays and visually scored lesions that were i) at least 8 consecutive SNP positions in length and ii) either all blue (indicating less than 2N copy estimates=losses) or all red (indicating greater than 2N copy estimates=gains). Sensitivities and specificities for the visual lesion calling method were calculated against the clinical FISH data for del17p, del13q14, trisomy 12 and del11q as the gold standard. Sensitivities and specificities for (SNM/PDO) were [(94%/93%) and (93%/91%)] for del13q14, [(88%/88%) and (98%/98%)] for trisomy 12, [(100%/100%) and (99%/99%)] for del17p, and [(100%/100%) and (99%/100%)] for del11q, and ii) algorithmic detection of gains and losses using search methods optimized for detection using FISH-based del13q14 lesions as the gold standard. We devised a sliding window algorithm that scores a lesion as “copy loss” when a SNP window of 8 consecutive SNPs has at least 6 SNPs with a copy number estimate of 1.32 or less (the 8/6/1.32 rule). For validation, an approximately 5 Mb-long physical window was selected, overlapping with all described del(13q14) lesions. Defining an algorithmic del(13q14) call as any patient for whom the 8/6/1.32 rule identified at least one lesion within the 5Mb window, we achieved 81% sensitivity and 96% specificity for detecting or excluding 13q14 lesions as measured against the clinical FISH panel. Results: Within the group of 117 patients, 22(19%), 15(13%), 12(10%) and 10(9%) had visual complexity scores of equal to or greater than 2.5, 3, 3.5 or 4, respectively: a previously unanticipated degree of genomic complexity in CLL.In univariate analysis, CLL patients with four or more sub-chromosomal genomic lesions had a median TTFT of 15.8 months, whereas the median TTFT for all other patients was not reached in our study (two-sided p<10−4). In bivariate analysis, presence of genomic complexity defined a high-risk group of patients within the IgVH unmutated subgroup. Patients with unmutated IgVH/high complexity score had a TTFT of 16.5 months versus 95.6 months for unmutated IgVH/low complexity patients (p=0.02). Finally, high genomic complexity resulted in strong trends towards shorter TTFT for patients within other established risk groups.
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Orgel, Etan, Celia Framson, Rubi Vazquez, David R. Freyer, and Steven D. Mittelman. "Age but Not Adiposity Predicts Asparaginase-Induced Hepatotoxicity during Induction Therapy for Adolescent and Young Adults with Acute Lymphoblastic Leukemia." Blood 132, Supplement 1 (2018): 2662. http://dx.doi.org/10.1182/blood-2018-99-110268.
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Abstract INTRODUCTION: Obesity is associated with increased treatment-related toxicity during therapy for acute lymphoblastic leukemia (ALL). During induction, hepatotoxicity due to L-asparaginase results in significant morbidity and chemotherapy delays/modifications. While hepatotoxicity is more common in older adolescent and young adult (AYA) patients, it cannot be predicted with high accuracy. Obesity defined by the surrogate marker of body mass index (BMI) has been shown to be a risk factor for hepatotoxicity; however, BMI does not accurately reflect body adiposity during ALL therapy due to concurrent muscle loss and adiposity gain. Because excess adiposity is generally believed to be responsible for most of the comorbidities of obesity, we hypothesized that body fat measured by direct assessment would be a better predictor of asparaginase-induced hepatotoxicity, and that non-obese patients with increased adiposity might be identified as an at-risk population which would not otherwise be recognized. METHODS: We conducted an interim analysis of a prospective trial for an obesity intervention in pre-adolescent and AYA patients ≥10 years old newly diagnosed with B-ALL (NCT02708108). Whole-body dual-energy x-ray absorptiometry (DXA) performed at diagnosis and end of induction (EOI) directly quantified adiposity as total body fat percentage (TBF%) and fat mass (FM). Overweight or obesity (OW/OB) was defined using CDC-norms as a BMI percentile (BMI%) ≥85%. All patients were treated with Children's Oncology Group ALL regimens using a four-drug induction inclusive of glucocorticoids, daunorubicin, vincristine, and pegylated L-asparaginase. Obese and/or patients ≥15 years were considered at-risk for hepatotoxicity and thus eligible to receive exogenous supplementation with levocarnitine for hepatoprotection per provider discretion. The primary endpoint for the analysis was CTCAE Grade 3+ hepatotoxicity. Stepwise multivariable logistic regression models were constructed for the primary endpoint inclusive of TBF% and FM at diagnosis, change in FM during induction, and demographic candidate predictors. All tests were two-sided and significance was set at p<0.05. RESULTS: We analyzed a cohort of 25 subjects enrolled on trial with DXA results at diagnosis. The cohort was divided equally by age ≥15 years (48%) and sex (44% female). The majority were of Hispanic ethnicity (64%) consistent with institutional demographics. Over half the cohort was OW/OB at diagnosis with mean TBF% of 39.5±1.3% and FM 31.7±2.5kg. In this AYA population, Grade 3+ hepatotoxicity occurred in 10/25 (40%) overall; all episodes included transaminitis (10/10) ± concurrent hyperbilirubinemia (2/10). Two of these patients met criteria for CTCAE Grade 4 hepatotoxicity (2/25, 8%); both were older, obese, with TBF% >40% at diagnosis. After accounting for age, radiographic measures of adiposity at diagnosis were not significant predictors of hepatotoxicity on multivariable analyses (FM at diagnosis p=0.299; TBF% at diagnosis p=0.599). Similarly, gain or loss of FM was not significantly associated with hepatotoxicity after adjusting for age or starting BMI category (p=0.818). Successful loss of fat due to the intervention occurred in 7/13 (54%) of OW/OB patients (mean loss -3.9±8.9kg) but was similarly not associated with decreased risk of hepatotoxicity (p=0.734). Only age ≥15 years was significantly associated with risk for Grade 3 hepatotoxicity across all models. Levocarnitine supplementation was prescribed by the primary providers to five of six eligible at-risk patients; no reported adverse events occurred. No severe, CTCAE Grade 4 hepatotoxicity occurred in the four patients adherent to levocarnitine supplementation. CONCLUSION: Contrary to our hypothesis, neither directly measured adiposity at diagnosis nor changes in adiposity during ALL induction predicted hepatotoxicity for this AYA cohort. Older AYA patients were at significant risk for hepatotoxicity irrespective of level of adiposity. However, the potential impact of extreme obesity on hepatotoxicity requires further investigation. Validation of these results is necessary in a larger cohort; should they be confirmed, future trials targeting hepatotoxicity reduction from ALL induction should focus on age-related differences in drug metabolism and effects. Disclosures No relevant conflicts of interest to declare.
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Rawstron, Andy, Claudia Fazi, Neus Villamor, et al. "A Complementary Role of High Throughput Sequencing and Multiparameter Cytometry for Minimal Residual Disease (MRD) Detection in Chronic Lymphocytic Leukemia (CLL):an European Research Initiative (ERIC) Study." Blood 124, no. 21 (2014): 1976. http://dx.doi.org/10.1182/blood.v124.21.1976.1976.
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Abstract BACKGROUND. The detection of minimal residual disease (MRD) at the level of 0.01%/10-4 or above is a strong independent predictor of reduced progression-free (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy. Although newer agents such as B-cell receptor pathway inhibitors can result in prolonged survival without achieving complete response, there remains a important role for MRD analysis in assessing therapeutic strategies aimed at disease eradication and cure. This is particularly important in front-line trials for fit patients which now require at least five years of follow-up if PFS is used as an endpoint. The feasibility of using MRD as a surrogate or intermediate endpoint for accelerated approval of new treatments is under review by regulatory agencies but further prospective validation is required. At the same time technology is rapidly evolving and high-throughput sequencing (HTS) technologies now detect MRD at the 0.0001%/10-6 level. It is therefore important to determine the most effective approaches for quantifying MRD that are compatible with previous studies but sufficiently sensitive for current treatments. AIMS. This collaborative project had two objectives. First, to identify the simplest and most flexible flow cytometry panel capable of detecting MRD at the 0.01%/10-4 or lower, that is compatible with published data and independent of instrument/reagent manufacturer. Second, to compare the flow cytometry approach with HTS analysis using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). METHODS AND RESULTS. A core panel of antibodies for MRD detection was identified by testing an 8-marker combination in 52 samples (27 post-treatment and 25 dilution study) and re-analysing data with serial exclusion of single markers to determine redundancy. A 1-tube core panel of CD19, CD20, CD5, CD43, CD79b, and CD81 was identified and validated against the previously published 2-tube 6-marker and 4-tube 4-marker ERIC panels in 76 samples (19 post-treatment and 57 dilution study). The results showed good concordance (for log-transformed data above the LoQ, linearity=0.977, Pearson correlation co-efficient=0.983, average difference=0.026 log, 95% limit of agreement 0.20log) and a limit of detection of 0.001%/10-5 for the 1-tube core panel. Inter-operator variation was similar to CML MRD monitoring with both experienced operators, or inexperienced cytometrists after ~1 hour of specific education, achieving a 95% limit of agreement less than 0.3log in samples with MRD levels ranging from 0.0001 – 100%. The flow cytometry approach was compared with the ClonoSEQ HTS assay in 109 samples (21 dilution study and 88 post-treatment samples, complete data currently available on 13/88). The assay was applicable to the vast majority CLL patients, often with two clonal markers. There was 94% concordance at the 0.01% (10-4) threshold (15 samples with ≥0.01% CLL by both methods, 14 samples with <0.01% by both methods, 1 sample with 0.03% CLL by HTS and <0.003% CLL by flow cytometry, and 1 sample with 0.005% CLL by HTS and 0.012% by flow cytometry. HTS detected CLL IGH sequences in 22% (7/31) samples with no detectable CLL cells by flow cytometry (i.e. CLL level 0.0001-0.001%, 3/13 patient samples and 4/18 dilution samples). HTS demonstrated a relatively high variability in quantification, as seen in previous studies, but with a clear superiority in the limit of detection and good linearity (linearity=0.905, Pearson correlation co-efficient=0.870, average difference=0.078 log, 95% limit of agreement 1.5 log). CONCLUSIONS. The 1-tube 6-marker flow cytometry core panel is compatible with published studies, manufacturer-independent and flexible, providing directly quantitative results to 0.001%/10-5 without requiring a pre-treatment sample. HTS requires further work to standardise the quantitative analysis and prospective validation but the ClonoSEQ assay is applicable to >95% of CLL patients, does not require viable cells and is extremely sensitive, detecting residual disease in a significant proportion of cases with <0.01% CLL. The results indicate that flow cytometry and HTS are complementary technologies with a combined approach offering the most reliable way of quantifying CLL at the 0.01%/10-4 threshold while allowing higher sensitivity in clinical trials aimed at disease eradication. Disclosures Rawstron: Roche: Honoraria; Biogen Idec: Consultancy; Gilead: Consultancy, Honoraria; Abbvie: Honoraria; BD Biosciences: Intrasure reagent Patents & Royalties; Celgene: Honoraria; GSK: Honoraria. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sanders:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Hallek:Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Gilead: Honoraria. Hillmen:Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.
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Smith, B. Douglas, Andrew W. Roberts, Gail J. Roboz, et al. "Minimal Residual Disease (MRD) As Exploratory Endpoint in a Phase 1 Study of the Anti-CD123 Mab CSL362 Given As Post-Remission Therapy in Adult Acute Myeloid Leukemia (AML)." Blood 126, no. 23 (2015): 3819. http://dx.doi.org/10.1182/blood.v126.23.3819.3819.
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Abstract Background AML patients (pts) who achieve a morphologic complete remission (CR) may have MRD in bone marrow (BM) and/or peripheral blood detected as patient-specific leukemia-aberrant immunophenotype by multiparameter flow cytometry (MFC) or as abnormal transcripts of AML gene mutations/translocations by quantitative RT-PCR. Presence of MRDafter induction and/or consolidation therapy identifies pts at high risk of relapse, with increasing MRD levels indicating impendingrelapse in individual pts. Although standardized testing and validated endpoints for MRD determination across institutions are lacking, major cancer treatment centers can diagnose and track MRD reliablywhen assessed in serial BM samples. CD123 (IL3-Rα) is overexpressed by AML blasts and leukemia stem cells (LSC), suggesting that agents designed to target and kill CD123+ AML LSC and blasts may eliminate MRD and delay or prevent relapse. Retrospective clinical data suggest that conversion of AML pts from MRD + to MRD negative (-) status may confer clinical benefit; however this has not been fully characterized in prospective clinical trials. Methods CSL362 is a fully humanized, anti-CD123 monoclonal antibody, Fc domain-engineered to bind with high affinity to CD16 on natural killer (NK) cells. CSL362 activates antibody-dependent cell-mediated cytotoxicity (ADCC) of CD123+ cells. The first-in-human Phase 1 study of CSL362 assessed safety, PK and targeted bioactivity. An exploratory objective was to track changes in MRD and to correlate changes with maintenance of CR. Eligible pts had CD123+ de novo or secondary AML in 1st or 2nd CR or CRp who recovered from induction with or without consolidation therapy, had risk factors prognostic for early relapse, and were not candidates for hematopoietic stem cell transplantation. CSL362 was infused IV over 3 hours once every 14 days for up to 6 doses. Sequential pt cohorts were treated at ascending dose levels from 0.3 to 12.0 mg/kg. The final safety evaluation visit was at week (wk) 16, and each center reported remission status at wk 24 from first dose. BMwas assayed for MRD at baseline as well as in wk 5 and wk 12 during therapy according to individual site's laboratory standards using MFC and/or PCR. Changes in MRD were compared to the baseline result for each pt. Results Enrollment completed with 30 pts total, in 6 dose level cohorts, treated at 4 hospitals. Safety, PK and biomarker results showing an acceptable safety profile, and targeted bioactivity of CSL362 were reported at the ASH 2014 Annual Meeting [Blood 124 (21); 120]. At baseline, 12 pts were MRD+ (5 by MFC only, 4 by PCR only and 3 by both methods); 11 of 12 had a follow up evaluation. Molecular mutations in post-remission BM identified by PCR were FLT3 (3 pts), NPM1 (3 pts) and MLL (1 pt). Of 4 pts MRD+ by MFC only, 1 converted to MFC- and maintained CR at wk 24. Of 4 pts MRD+ by PCR only, 1 converted to PCR- and maintained CR at wk 24; a 2nd pt, who remained PCR+ on study also maintained CR at wk 24. Of 3 pts MRD+ by both MFC and PCR, 1 converted to MFC-, PCR follow-up was not done but the pt maintained CR at wk 24. The 7 pts MRD+ who did not convert to MRD- relapsed prior to wk 24. [See table]. Table 1. MRD+ at baseline Converted to MRD - at Wk 5 Converted to/Maintained MRD - at Wk 12 Maintained CR at Wk 24 4 + by MFC only 1 2 1 4 + by PCR only (1 FLT3, 1 MLL, 2 NPM1) 0 1 (NPM1) 2 (NPM1; MLL) 3 + by MFC & PCR (2 FLT3, 1 NPM1) by MFC 3by PCR 0 by MFC 1by PCR 0 1 (Flt3) Discussion Conversion from MRD + to MRD - in 4 of 11 pts, with CR maintained at wk 24, is hypothesis generating; MRD conversion suggests possible eradication of residual leukemia cells while on study. Maintenance of morphologic CR was more likely for patients who converted to a MRD-state than those who remained MRD+ during therapy. Multiple factors may affect AML response to CSL362 immunotherapy, including cytogenetic abnormalities, specific molecular mutations, and each pt's immune system status. Preclinical data suggest the activity of CSL362 requires adequate numbers and function of NK cells and expression of the target receptor (CD123) on LSC and MRD cells. This observation would provide validation for the use of MRD response as efficacy endpoint and indicator of benefit for CSL362 and, perhaps, other AML therapies. With further efforts to standardize AML MRD assessments across laboratories, MRD response may become useful as a surrogate endpoint for clinical drug development in AML. Disclosures DeWitte: CSL Behring: Employment. Dasen:CSL Behring: Employment. Bensen-Kennedy:CSL Behring: Employment. Walter:AstraZeneca, Inc.: Consultancy; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding.
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Catania, Gioacchino, Nicol Trincheri, Enrico Marco Gottardi, et al. "Prognostic Impact of p190 and p210 Co-Expression in Early Molecular Response in Chronic Myeloid Leukemia (CML) Patients Treated with Tyrosin Kinase Inibitors." Blood 128, no. 22 (2016): 5446. http://dx.doi.org/10.1182/blood.v128.22.5446.5446.
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Abstract Background: Expression of p190 BCR-ABL mRNA is generally considered to be confined to patients with acute lymphoid or more rarely myeloid leukemias, whereas p210 BCR-ABL mRNA is the hallmark of CML. In reality it is not uncommon the presence of p190 m-RNA in p210 CML in chronic phase, due to alternative or missplicing. Its presence seems to have no impact on prognosis in the pre-TKI era, although it may be expression of genomic instability. Aim: Primary object of this study was to investigate if the co-expression might influence the rate of early outcome surrogate endpoints such as such as optimal molecular response (EMR; BCR-ABL < 10% (IS) at 3 month and BCR-ABL < 1% or 6 month). in patients treated with TKI. Methods: Were evaluated patients with CML in chronic phase treated with TKI at our institution. We excluded cases with less than one year of treatment or treated with conventional chemotherapy. The fusion transcripts BCR-ABL were evaluated at diagnosis in peripheral blood by NESTED-PCR and the molecular response were evaluated in peripheral blood with Real-Time PCR. The patients were divided into two groups, "double transcripts" (DT) and "single transcript" (ST). Results: A total of 34 patients were analyzed. The median age was 61 years (range 22-80) and 26 (68%) were male. Ten patients (29%) were DT and twenty-fouru(71%) ST. The distribution according to Sokal score was: 2 (10%), 5 (50%) 3(30%) patients for low, intermediate and high risk in the DT, whereas 13 (54%), 10 (41%) 1 (5%) low, intermediate and high risk in ST, respectively. The optimal response at 3 month was achieved in 3 patients with DT and 20 patients with ST ( 10% vs 83), at 6-month optimal response was achieved in 3 patients with DT and 20 patients with ST (10% vs 83). No patients with BCR-ABL > 10 % at 3 months, achieved molecular response at 6 months. Summary/Conclusion: In our study the co-expression of p190 and p210 BCR-ABL transcripts influences the early molecular response to TKI and suggesting the need for a larger validation study Disclosures No relevant conflicts of interest to declare.
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Ciani, Oriana, Bogdan Grigore, Hedwig Blommestein, et al. "Validity of Surrogate Endpoints and Their Impact on Coverage Recommendations: A Retrospective Analysis across International Health Technology Assessment Agencies." Medical Decision Making 41, no. 4 (2021): 439–52. http://dx.doi.org/10.1177/0272989x21994553.
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Background Surrogate endpoints (i.e., intermediate endpoints intended to predict for patient-centered outcomes) are increasingly common. However, little is known about how surrogate evidence is handled in the context of health technology assessment (HTA). Objectives 1) To map methodologies for the validation of surrogate endpoints and 2) to determine their impact on acceptability of surrogates and coverage decisions made by HTA agencies. Methods We sought HTA reports where evaluation relied on a surrogate from 8 HTA agencies. We extracted data on the methods applied for surrogate validation. We assessed the level of agreement between agencies and fitted mixed-effects logistic regression models to test the impact of validation approaches on the agency’s acceptability of the surrogate endpoint and their coverage recommendation. Results Of the 124 included reports, 61 (49%) discussed the level of evidence to support the relationship between the surrogate and the patient-centered endpoint, 27 (22%) reported a correlation coefficient/association measure, and 40 (32%) quantified the expected effect on the patient-centered outcome. Overall, the surrogate endpoint was deemed acceptable in 49 (40%) reports ( k-coefficient 0.10, P = 0.004). Any consideration of the level of evidence was associated with accepting the surrogate endpoint as valid (odds ratio [OR], 4.60; 95% confidence interval [CI], 1.60–13.18, P = 0.005). However, we did not find strong evidence of an association between accepting the surrogate endpoint and agency coverage recommendation (OR, 0.71; 95% CI, 0.23–2.20; P = 0.55). Conclusions Handling of surrogate endpoint evidence in reports varied greatly across HTA agencies, with inconsistent consideration of the level of evidence and statistical validation. Our findings call for careful reconsideration of the issue of surrogacy and the need for harmonization of practices across international HTA agencies.
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Rossi, Davide, Silvia Rasi, Claudio Tripodo, et al. "Host Genetic Background and Risk of Richter Syndrome: The Genotype of LRP4 Is An Independent Predictor of Chronic Lymphocytic Leukemia Transformation to Aggressive Lymphoma." Blood 114, no. 22 (2009): 2340. http://dx.doi.org/10.1182/blood.v114.22.2340.2340.
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Abstract Abstract 2340 Poster Board II-317 Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Mechanisms and risk factors of CLL transformation to RS are known only in part. This study aimed at exploring the role of the host genetic background in RS transformation and was based on a consecutive series of 331 CLL, of which 21 had transformed to RS (all clonally related to the CLL clone). Twenty eight additional cases of clonally related RS were also collected for validation purposes. Using an educated guess approach, SNPs were selected according to the following criteria: i) reported association with CLL prognosis; ii) minor allele frequency >5% in Caucasians. Accordingly, 45 SNPs from 45 genes (APOE, BARD1, BRCA2, CD5, CPA4, CPT2, CYP2C9, CD38, DUSP13, ENPP5, ERBB2IP, ERCC5, ERCC6 ESPL1, FHL5, FOXN1, GALNACT2, GTF2E1, HIPK4, IL16, IL19, INHBC, KLRC4, KRT1, LAMA2, LILRA4, LRP2, LRP4, MDM2, MGMT, MMP10, MYBPC3, PMS2, POLB, SEC23B, SEMA3C, THBS1, TOPBP1, TYR, USP47, XRCC2, ZNF169, ZNF527, ZNF573, IRF4) were genotyped by SNP-minisequencing. The primary endpoint of the study was cumulative probability of transformation measured from CLL diagnosis to RS transformation, death or last follow-up. Univariate Cox analysis controlled for multiple comparisons by FDR testing identified LRP4 rs2306029, a SNP affecting the low density lipoprotein receptor protein 4 gene, as the sole SNP associated with RS transformation. CLL who carried LRP4 rs2306029 TT variant genotype displayed a higher risk of transformation (Events/N: 12/79; 5-year risk: 14.1%) compared to patients carrying the LRP4 rs2306029 CT/CC genotypes that contained the wild type allele (Events/N: 9/252; 5-year risk: 4.7%) (HR:4.08; p<.001; q=.040) (Fig. 1). Other variables at CLL diagnosis associated with an increased risk of RS were advanced Binet stage (p<.001), lymph node size >3 cm, LDH elevation (p<.001), CD38 expression (p=.010), ZAP70 expression (p=.017), unfavorable FISH karyotype (p<.001), IGHV homology >98% (p<.001), and stereotyped HCDR3 (p<.001). None of the patient subgroups carrying the above risk factors was enriched with the LRP4 rs2306029 TT variant genotype (p>.050 in all instances), suggesting that LRP4 rs2306029 TT is not a surrogate of other RS risk factors. Multivariate Cox analysis selected LRP4 rs2306029 TT as an independent predictor of RS (HR:5.66; p<.001), along with stereotyped HCDR3 (HR:5.02; p=.001), and CD38 expression (HR:3.47; p=.011). LRP4 rs2306029 genotyping in an independent RS series (n=28) collected for validation purposes confirmed the enrichment of TT genotype and T alleles observed in the original RS series (TT genotype: 11/28 39.2% vs 12/21, 57.1%; p=.139; T allele: 60.7% vs 64.3%; p=.811). To date, the sole other host genetic factor associated with RS transformation is the CD38 rs6449182 SNP (Aydin et al, Blood 2008; 111: 5646). LRP4 rs2306029 and CD38 rs6449182 genotypes displayed statistical interaction and identified CLL subgroups at different risk of transformation (p=.043). LRP4 rs2306029 is a non-synonymous SNP mapping to exon 31 of LRP4 and leading to Ser1554Gly amino acid substitution. In silico analysis with PupaSuite, PolyPhen, and SNPeffect algorithms predicted LRP4 rs2306029 T variant allele to have functional effect on LRP4 protein. In silico elaboration of public data sets revealed that LRP4 gene expression levels did not differ among LRP4 rs2306029 genotypes (p=.743). LRP protein expression in CLL is unknown and was analyzed in 26 cases. By flow cytometry, LRP4 was expressed in all cases with a median percentage of expression of 92.0% and a MFI of 78.0 that did not vary among genotypes (p=.527 and p=.964, respectively). By immunohistochemistry on bone marrow biopsies, LRP4 showed an expression pattern that varied according to genotype of the rs2306029 SNP, being cytoplasmic in CLL carrying the T allele and nuclear in CLL carrying the CC genotype. The conclusion of our study are threefold: i) LRP4 rs2306029 TT genotype is an independent predictor of CLL transformation to RS; ii) LRP4 protein is expressed in CLL cells; iii) LRP4 rs2306029 genotype may affect the expression pattern of LRP4 in CLL cells. Since LRP4 is involved in suppressing Wnt signalling, the LRP4 rs2306029 T variant may have pathogenetic relevance for RS development. Disclosures: No relevant conflicts of interest to declare.
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Green, EM, G. Yothers, and Daniel J. Sargent. "Surrogate endpoint validation: statistical elegance versus clinical relevance." Statistical Methods in Medical Research 17, no. 5 (2008): 477–86. http://dx.doi.org/10.1177/0962280207081863.
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Burzykowski, Tomasz, and Marc Buyse. "Surrogate threshold effect: an alternative measure for meta-analytic surrogate endpoint validation." Pharmaceutical Statistics 5, no. 3 (2006): 173–86. http://dx.doi.org/10.1002/pst.207.
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Liu, WP, and L. Pacheco. "POSB285 Five Identified Hurdles Associated with Surrogate Endpoint Validation." Value in Health 25, no. 1 (2022): S182. http://dx.doi.org/10.1016/j.jval.2021.11.887.
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Bebu, Ionut, Thomas Mathew, and Brian Agan. "Inference for Surrogate Endpoint Validation in the Binary Case." Journal of Biopharmaceutical Statistics 25, no. 6 (2015): 1272–84. http://dx.doi.org/10.1080/10543406.2015.1008516.
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Trock, Bruce J. "Validation of surrogate endpoint biomarkers in prostate cancer chemoprevention trials." Urology 57, no. 4 (2001): 241–47. http://dx.doi.org/10.1016/s0090-4295(00)00983-3.
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Huang, Guan-Hua, Chin-Chiang Hsieh, Chen-Hsin Chen, and Wei J. Chen. "Statistical validation of endophenotypes using a surrogate endpoint analytic analogue." Genetic Epidemiology 33, no. 6 (2009): 549–58. http://dx.doi.org/10.1002/gepi.20407.
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Komrokji, Rami S., Amy E. DeZern, Katrina Zell, et al. "Validation of International Working Group (IWG) Response Criteria in Higher-Risk Myelodysplastic Syndromes (MDS): A Report on Behalf of the MDS Clinical Research Consortium (MDS CRC)." Blood 126, no. 23 (2015): 909. http://dx.doi.org/10.1182/blood.v126.23.909.909.
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Introduction The primary goal for treatment of higher-risk MDS patients (pts) is to improve overall survival (OS) and delay acute myeloid leukemia (AML) evolution. The IWG 2006 response criteria are used in clinical trials and in clinical practice for assessing efficacy of MDS therapies. These criteria were originally proposed by an international group of experts based on available data and consensus. In an ad hoc landmark analysis of the AZA-001 study using the 2006 IWG criteria, pts who achieved hematological improvement (HI), complete response (CR), marrow CR (mCR), or partial response (PR) demonstrated improved OS. The aim of this study is to validate the IWG 2006 response criteria among a large cohort of higher-risk MDS pts. Methods Pts with higher-risk MDS (intermediate-2 (Int-2) or High Risk by International Prognostic Scoring System (IPSS)) who had received treatment and for whom details of response and outcome were available were included from the MDS CRC database. Pts were also classified per IPSS-R. The best response to treatment was categorized per the published IWG 2006 response criteria as CR, PR, mCR, HI, stable disease (SD) or progressive disease (PD). The primary endpoint was OS. Results We identified 646 treated higher-risk MDS pts. Table-1 summarizes baseline characteristics. The first line treatment was hypomethylating agent-based therapy (HMA) in 470 pts (74%). The median duration of follow up was 23.2 months (mo) (95% CI: (19.9, 26.5). Median OS from diagnosis was significantly longer for pts with int-2 IPSS risk disease IPSS (26.2 mo (21.5, 29.7)) compared to those who were High Risk (18.8 mo (15.9, 23.6); (p = 0.026). Median OS from diagnosis also differed by IPSS-R category (p < 0.001): for pts with Low risk (n = 6) it was not reached; Intermediate risk it was 41.7 mo (31.8, NR); High Risk it was 28.4 mo (24.1, 33.2); and for pts with Very High it was 16.5 mo (15.3, 19.1). The best IWG 2006 response rate for first line therapy among evaluable pts (n=597) was CR in 93 pts (16%), mCR in 10 (2%), PR in 57(10%), HI in 60 (10%), SD in 233 (39%), and PD in 144 (24%). The median OS based on IWG 2006 best response for first line therapy was 41 mo for CR, 12 mo for mCR, 26 mo for PR, 13 mo for HI, 14 mo for SD and 7 mo for PD. (p <0.001). CR was associated with better outcome compared to all other response groups. Pts with PR, HI, and SD had better outcome compared to PD, and similar outcome among the 3 groups. There was no difference in rate of AML transformation among response groups except in PD pts compared to others. For pts who were treated with HMA as first line therapy, the best response rates by IWG 2006 criteria were CR in 15%, mCR in 2%, PR in 10%, HI in 12%, SD in 40% and PD in 21%. Median OS in mo from time of HMA therapy based on response was: CR 19 (16.3, NR), mCR: 9 (7.1, NR), PR: 13 (8.8, NR), HI: 11 (7.7, 19.0), SD: 11.0 (8.5, 12.6), and PD: 3 (2.3, 3.9). (p <0.001) The best response by IWG 2006 criteria remained predictive of OS after adjusting for IPSS-R risk group. HR 0.30 (95% CI 0.2-0.4) for CR, and 0.57 (95% CI 0.45-0.7) for mCR/PR/HI compared to PD, (p <0.001) Conclusions: The best response by IWG 2006 criteria to first line therapy in higher-risk MDS correlates with OS. Pts who achieved CR had the best OS, while pts who achieved SD or better response had improved outcome compared to PD, with mCR having an OS equivalent to SD. The CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS pts in randomized Phase II studies determining comparison arms of Phase III trials, and for regulatory purposes. Table 1. Baseline characteristics Variable Total n=646 Age Median 68 Gender Male 399/645(62%) Race White 566/633 (89%) t-MDS Yes 161/545/514 (30%) WHO RA RARS RCMD RAEB-I RAEB-II MDS-U MDS/MPN CMML 5/527 (1%) 7/527 (1%) 69/527 (13%) 1153/527 (29%) 284/527 (54%) 3/527 (1%) 5/527 (1%) 1/527 (1%) IPSS Intermediate-II High 468/646 (72%) 178/646 (28%) R-IPSS Very low Low Intermediate High Very High 0 6/621 (1%) 74/621 (12%) 211/621 (34%) 330/621 (53%) IPSS karyotype Good Intermediate Poor 135/642 (21%) 118/642 (18%) 389 /642 (61%) IPSS-R karyotype Very good Good Intermediate Poor Very poor 7/642 (1%) 137/642 (21%) 134/642 (21%) 118/642 (18%) 246/642 (38%) Allogeneic transplant Yes 158/554 (29%) First line therapy HMA Chemotherapy IMiDClinical trial other 470/634 (74%) 57/634 (9%) 43/634 (7%) 25/634 (4%) 38/634 (6%) Lab (mean) Hgb (n=514) Platelets (n=514) ANC (n=514) Bone marrow blasts (n=639) 9.2 94 1.6 10% Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy; Pharmacylics: Speakers Bureau; Celgene: Consultancy, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
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Wagner, John A. "Overview of Biomarkers and Surrogate Endpoints in Drug Development." Disease Markers 18, no. 2 (2002): 41–46. http://dx.doi.org/10.1155/2002/929274.
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There are numerous factors that recommend the use of biomarkers in drug development including the ability to provide a rational basis for selection of lead compounds, as an aid in determining or refining mechanism of action or pathophysiology, and the ability to work towards qualification and use of a biomarker as a surrogate endpoint. Examples of biomarkers come from many different means of clinical and laboratory measurement. Total cholesterol is an example of a clinically useful biomarker that was successfully qualified for use as a surrogate endpoint. Biomarkers require validation in most circumstances. Validation of biomarker assays is a necessary component to delivery of high-quality research data necessary for effective use of biomarkers. Qualification is necessary for use of a biomarker as a surrogate endpoint. Putative biomarkers are typically identified because of a relationship to known or hypothetical steps in a pathophysiologic cascade. Biomarker discovery can also be effected by expression profiling experiment using a variety of array technologies and related methods. For example, expression profiling experiments enabled the discovery of adipocyte related complement protein of 30 kD (Acrp30 or adiponectin) as a biomarker forin vivoactivation of peroxisome proliferator-activated receptors (PPAR)γactivity.
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Candida Fratazzi and Jixiao Niu. "Accelerated orphan drug approval: surrogate endpoints." World Journal of Advanced Pharmaceutical and Medical Research 2, no. 1 (2022): 001–7. http://dx.doi.org/10.53346/wjapmr.2022.2.1.0021.
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Today, orphan drug development is confronted with significant challenges represented by the considerable complexity, diversity of clinical manifestations, and competition in study recruitment. Thus, surrogate endpoints adoption plays a crucial role in rare disease trials by minimizing costs, the number of subjects, and study duration. Surrogate endpoints, to substitute for a direct measure of how patients feel, function, or survive, must be biomarkers that directly correlate with disease clinical manifestations and predict the impact of study drug on the long-term disease progression. Validation of surrogate endpoints for accuracy and sensitivity is essential to maximize its benefit and utility. These validation criteria include reliability, reproducibility, keenness, and a direct reflection of patient feeling, function, or survival upon treatment. On the other hand, the selection of surrogate endpoints may be pretty complex, and making mistakes may lead to inaccurate estimates of the clinical benefit. Finally, surrogate endpoints contribute to a composite endpoint when studying drug benefits patients in multiple ways, and not all the measured components are detected in each patient. Furthermore, a composite endpoint comprised of multiple surrogate endpoints could improve statistical efficiency. Selection and qualification of biomarkers for surrogate endpoints and accelerated market approval is often a complex process that requires experience and method. Today, we contributed to developing orphan drugs for many rare diseases, including Neurological Diseases, Lysosomal Storage Diseases, Metabolic Conditions, Immune Disorders, and Cancers. In conclusion, surrogate endpoints play an essential role in orphan drug development, benefiting patients and the healthcare system.
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Ciani, Oriana, Sarah Davis, Paul Tappenden, et al. "VALIDATION OF SURROGATE ENDPOINTS IN ADVANCED SOLID TUMORS: SYSTEMATIC REVIEW OF STATISTICAL METHODS, RESULTS, AND IMPLICATIONS FOR POLICY MAKERS." International Journal of Technology Assessment in Health Care 30, no. 3 (2014): 312–24. http://dx.doi.org/10.1017/s0266462314000300.
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Objectives: Licensing of, and coverage decisions on, new therapies should rely on evidence from patient-relevant endpoints such as overall survival (OS). Nevertheless, evidence from surrogate endpoints may also be useful, as it may not only expedite the regulatory approval of new therapies but also inform coverage decisions. It is, therefore, essential that candidate surrogate endpoints be properly validated. However, there is no consensus on statistical methods for such validation and on how the evidence thus derived should be applied by policy makers.Methods: We review current statistical approaches to surrogate-endpoint validation based on meta-analysis in various advanced-tumor settings. We assessed the suitability of two surrogates (progression-free survival [PFS] and time-to-progression [TTP]) using three current validation frameworks: Elston and Taylor's framework, the German Institute of Quality and Efficiency in Health Care's (IQWiG) framework and the Biomarker-Surrogacy Evaluation Schema (BSES3).Results: A wide variety of statistical methods have been used to assess surrogacy. The strength of the association between the two surrogates and OS was generally low. The level of evidence (observation-level versus treatment-level) available varied considerably by cancer type, by evaluation tools and was not always consistent even within one specific cancer type.Conclusions: Not in all solid tumors the treatment-level association between PFS or TTP and OS has been investigated. According to IQWiG's framework, only PFS achieved acceptable evidence of surrogacy in metastatic colorectal and ovarian cancer treated with cytotoxic agents. Our study emphasizes the challenges of surrogate-endpoint validation and the importance of building consensus on the development of evaluation frameworks.
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Hopkinson, D., C. Chadwick, M. Bibi, and A. Bastian. "Review of Surrogate Endpoint Validation Methodologies and Application In Solid Tumour Htas." Value in Health 20, no. 9 (2017): A731. http://dx.doi.org/10.1016/j.jval.2017.08.1994.
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Woods, Gail, Marisa Miceli, Monica Grazziutti, et al. "Validation of Serum Aspergillus Galactomannan Index as a Surrogate Endpoint for Outcome of Invasive Aspergillosis: Clinical and Research Implications." Blood 108, no. 11 (2006): 2861. http://dx.doi.org/10.1182/blood.v108.11.2861.2861.
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Abstract Background: Assessing clinical outcome of aspergillosis with conventional clinical and laboratory criteria is difficult. A composite “global outcome response” (clinical, radiologic, pathologic and microbiologic criteria) is frequently used but suffers from poor sensitivity and specificity, and has not been standardized or validated. A reliable, quantitative, non-invasive, and easy to measure laboratory test than can substitute for this composite endpoint, i.e. serve as a surrogate endpoint for aspergillosis outcome is highly desirable. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. The test which is reported as an index of optical density (OD) is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome. Purpose: To evaluate serum GMI as a surrogate endpoint for outcome of invasive aspergillosis in patients with hematological cancer. Patients and Methods: patients at risk for aspergillosis (11/03-2/06) underwent GMI screening during periods at risk. The clinical and laboratory findings of patients with ≥ 2 (+) GMI (OD ≥ 0.5) were reviewed. To validate GMI as a surrogate endpoint for aspergillosis, a k correlation concordance coefficient test between GMI and an objective clinical outcome of aspergillosis (death) was applied. The correlation is considered perfect when k is 1.0; excellent when ≥ 0.75. Results: 30 patients had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Aspergillosis developed following stem cell transplantation [autologous (11), allogeneic (1)], or after conventional chemotherapy (18). Among 25 neutropenic patients (<1000/ml), persistent GMI elevation was associated with death (5/5 patients) while return to negative values predicted survival (20/20 patients). Among 5 non-neutropenic patients, 1 with persistently elevated GMI died compared to no death among the remaining 4 whose GMI became negative. Overall, the GMI correlated with clinical outcome in all 30 patients with a perfect 1.0 k correlation concordance coefficient. Conclusion: we have validated GMI as an excellent surrogate endpoint for the outcome of invasive aspergillosis among patients with hematological cancer. This FDA-approved test is reproducible, quantitative, non-invasive, easy to measure and widely available. These findings have important implications for patient care and for the design of clinical trials of mould-active antifungal agents.
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Santosh Kumar, Rada, and Ganesh Sai Myneni. "SURROGATE ENDPOINT: ALTERNATIVE FOR EARLY ASSESSMENT OF A POTENTIAL TREATMENT EFFECT." Journal of Drug Delivery and Therapeutics 9, no. 4-s (2019): 819–21. http://dx.doi.org/10.22270/jddt.v9i4-s.3371.
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The efficacy of health technologies, medicines and medical devices should be demonstrated in trails that evaluate final patient-relevant outcomes such as survival or morbidity. We provide a summary of the present use of surrogate end points in health care policy, discussing the case for and against their reviewing and adoption validation methods. Although the use of surrogates can be problematic, they can be validated and selected properly, offers important chances for more efficient clinical trials and faster access to new health technologies that benefit health care systems and patients. In early drug development studies, tumor response is often the true primary endpoint. Usually clinical trials are needed to show that it can be dependent upon to predict, or correlate with, clinical benefit in a context of use. Surrogate endpoints that have undergone this ample testing are called validated surrogate endpoints and these are accepted by the Food and Drug Administration as evidence of benefit. Choosing the right surrogate endpoint and proving that it can predict the intended clinical benefit, however, is not always straightforward. When a disease has been sufficiently studied, surrogate endpoints can measure the underlying cause of a disease (such as low thyroxine levels and hypothyroidism) or an effect that predicts the ultimate outcome (such as measuring diuresis, which is expected to improve symptoms of heart failure).
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Miksad, Rebecca A., Vera Zietemann, Raffaella Gothe, et al. "Progression-free survival as a surrogate endpoint in advanced breast cancer." International Journal of Technology Assessment in Health Care 24, no. 04 (2008): 371–83. http://dx.doi.org/10.1017/s0266462308080495.
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Objectives:Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint.Methods:A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROSfrom observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption.Results:Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n= 4,323) and seventeen T (n= 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROSand HRPFSwas 0.71 for A (p= .0029) and 0.75 for T (p= .0028). While HRPFSwas a statistically significant predictor of HROSfor both A (p= .0019) and T (p= .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROSagreed with observed HROSin 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses.Conclusions:This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.
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Renard, Didier, Helena Geys, Geert Molenberghs, et al. "Validation of a longitudinally measured surrogate marker for a time-to-event endpoint." Journal of Applied Statistics 30, no. 2 (2003): 235–47. http://dx.doi.org/10.1080/0266476022000023776.
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Pullen, Matthew F., Katherine Huppler Hullsiek, Joshua Rhein, et al. "Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials." Clinical Infectious Diseases 71, no. 7 (2020): e45-e49. http://dx.doi.org/10.1093/cid/ciaa016.
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Abstract Background In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. Methods We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010–2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. Results Mortality through 18 weeks was 37% for EFA &gt; = 0.60 (n = 170), 36% for 0.40–0.59 (n = 182), 39% for 0.30–0.39 (n = 112), 35% for 0.20–0.29 (n = 87), and 50% for those with EFA &lt; 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA &lt; 0.20 to those with EFA &gt; = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P &lt; .01) and lower proportion of patients with CSF pleocytosis (P &lt; .001). Conclusions EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of &gt; = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA &lt; 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.
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Deng, Yanhong, Yue Cai, Jianwei Zhang, et al. "Validation of neoadjuvant rectal cancer(NAR) score as a surrogate endpoint for disease free survival in Chinese FOWARC study." Journal of Clinical Oncology 37, no. 15_suppl (2019): e15162-e15162. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15162.
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e15162 Background: NAR score is considered as a surrogate endpoint for survival in patients with locally advanced rectal cancer who received neoadjuvant treatment. Here we validate it in Chinese FOWARC study, especially in the chemotherapy alone arm. Methods: NAR score is calculated based on cT, ypT, ypN as reported for patients who received surgery in FOWARC study. NAR score is correlated to DFS with COX regression and Kaplan-Meier analysis. Results: 451 patients had surgery, 147 in FU-RT group, 152 in FOLFOX-RT arm and 152 in FOLFOX arm. NAR score is a significant prognostic factor in COX regression (P=0.000, HR 1.034, 95% CI 1.024-1.045) and in FOLFOX alone group (p=0.001, HR 1.030, 95% CI 1.013-1.047). When NAR score is quartile to <5, 5-10, 10-15,>15, the survival of patients is listed below, and similar to pathological staging. Conclusions: NAR score can be used as a surrogate endpoint for disease free survival Chinese patients. But it is not superior to pathological stage, especially in patients who received chemotherapy alone. [Table: see text]
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Wang, Y. C., A. Sandrock, J. R. Richert, L. Meyerson, and X. Miao. "Short-Term Relapse Quantitation as a Fully Surrogate Endpoint for Long-Term Sustained Progression of Disability in RRMS Patients Treated with Natalizumab." Neurology Research International 2011 (2011): 1–6. http://dx.doi.org/10.1155/2011/195831.
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Time to sustained worsening in the expanded disability status scale as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect. Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test. This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year.
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Sertdemir, Y., and R. Burgut. "Does the decision in a validation process of a surrogate endpoint change with level of significance of treatment effect? A proposal on validation of surrogate endpoints." Contemporary Clinical Trials 30, no. 1 (2009): 8–12. http://dx.doi.org/10.1016/j.cct.2008.08.006.
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Ciani, Oriana, Massimo Piepoli, Neil Smart, et al. "Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure." JACC: Heart Failure 6, no. 7 (2018): 596–604. http://dx.doi.org/10.1016/j.jchf.2018.03.017.
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Caron, Melissa, Sabrina Hoa, Marie Hudson, Kevin Schwartzman, and Russell Steele. "Pulmonary function tests as outcomes for systemic sclerosis interstitial lung disease." European Respiratory Review 27, no. 148 (2018): 170102. http://dx.doi.org/10.1183/16000617.0102-2017.
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Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc). We performed a systematic review to characterise the use and validation of pulmonary function tests (PFTs) as surrogate markers for systemic sclerosis-associated interstitial lung disease (SSc-ILD) progression.Five electronic databases were searched to identify all relevant studies. Included studies either used at least one PFT measure as a longitudinal outcome for SSc-ILD progression (i.e. outcome studies) and/or reported at least one classical measure of validity for the PFTs in SSc-ILD (i.e. validation studies).This systematic review included 169 outcome studies and 50 validation studies. Diffusing capacity of the lung for carbon monoxide (DLCO) was cumulatively the most commonly used outcome until 2010 when it was surpassed by forced vital capacity (FVC). FVC (% predicted) was the primary endpoint in 70.4% of studies, compared to 11.3% for % predicted DLCO. Only five studies specifically aimed to validate the PFTs: two concluded that DLCO was the best measure of SSc-ILD extent, while the others did not favour any PFT. These studies also showed respectable validity measures for total lung capacity (TLC).Despite the current preference for FVC, available evidence suggests that DLCO and TLC should not yet be discounted as potential surrogate markers for SSc-ILD progression.
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Enweonye, Igwebuike, and Edith Uzoma Umeh. "Bayesian Meta-Analysis to Validate Correlate of Protection for High Vaccine Efficacy Clinical Trials." European Journal of Information Technologies and Computer Science 2, no. 1 (2022): 19–25. http://dx.doi.org/10.24018/compute.2022.2.1.34.
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In clinical trials, a correlate (surrogate) of protection (CoP) endpoint must be properly validated through rigorous sound methods before it may be approved for use. The validation of surrogate in the context of high vaccine efficacy trials, however, poses great challenge due to sparse data; and conventional methods for statistical validation of surrogate are no longer adequate. Although idea of surrogacy was developed in the context of a single trial, the meta-analytic approach, which allows both individual and trial level surrogacy, has become well accepted. However, the meta-analytic joint bivariate full models suffer computational issues. To ease the challenge, aggregate data may be used but it leads to loss of information. In this manuscript the direct application of individual level (instead of aggregate) data in a Bayesian Hierarchical Modelling framework was proposed. The proposed method uses reduced bivariate models with trial specific random effects of treatment on the endpoints and no correlated residuals. Simulated data consist several scenarios, each of which has 5000 participants data, 50 subgroups (used as trials) characterised by size of 100 participants per trial randomised in the ratio 1:1 to vaccinated and unvaccinated treatment groups. The meta-analysis showed improved quality of the CoP compared to literature based on aggregate data. There were no computational issues with the proposed hierarchical model.
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Meddi, Elisa, Arianna Savi, Federico Moretti, et al. "Measurable Residual Disease (MRD) as a Surrogate Efficacy-Response Biomarker in AML." International Journal of Molecular Sciences 24, no. 4 (2023): 3062. http://dx.doi.org/10.3390/ijms24043062.
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In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal post-remission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint.
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Funingana, Ionut-Gabriel, Pubudu Piyatissa, Marika Reinius, Cathal McCague, Bristi Basu, and Evis Sala. "Radiomic and Volumetric Measurements as Clinical Trial Endpoints—A Comprehensive Review." Cancers 14, no. 20 (2022): 5076. http://dx.doi.org/10.3390/cancers14205076.
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Clinical trials for oncology drug development have long relied on surrogate outcome biomarkers that assess changes in tumor burden to accelerate drug registration (i.e., Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria). Drug-induced reduction in tumor size represents an imperfect surrogate marker for drug activity and yet a radiologically determined objective response rate is a widely used endpoint for Phase 2 trials. With the addition of therapies targeting complex biological systems such as immune system and DNA damage repair pathways, incorporation of integrative response and outcome biomarkers may add more predictive value. We performed a review of the relevant literature in four representative tumor types (breast cancer, rectal cancer, lung cancer and glioblastoma) to assess the preparedness of volumetric and radiomics metrics as clinical trial endpoints. We identified three key areas—segmentation, validation and data sharing strategies—where concerted efforts are required to enable progress of volumetric- and radiomics-based clinical trial endpoints for wider clinical implementation.
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Kim, Heung Gon, Jose-Miguel Yamal, Xiao-Chun Xu, et al. "Cervical chromosome 9 polysomy: Validation and use as a surrogate endpoint biomarker in a 4-HPR chemoprevention trial." Gynecologic Oncology 99, no. 3 (2005): S32—S37. http://dx.doi.org/10.1016/j.ygyno.2005.07.039.
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You, Y. Nancy, Thomas J. George, Yi-Ju Chiang, et al. "Validation of neoadjuvant rectal cancer (NAR) score as a surrogate endpoint for overall survival in real-life practice settings." Journal of Clinical Oncology 36, no. 15_suppl (2018): 3517. http://dx.doi.org/10.1200/jco.2018.36.15_suppl.3517.
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Valicenti, R., M. Desilvio, G. Hanks, et al. "Surrogate endpoint for prostate cancer-specific survival: Validation from an analysis of Radiation Therapy Oncology Group Protocol 92–02." Journal of Clinical Oncology 23, no. 16_suppl (2005): 4549. http://dx.doi.org/10.1200/jco.2005.23.16_suppl.4549.
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Shinno, Yuki, Yasushi Goto, Sho Watanabe, et al. "Evaluation of time to failure of strategy as an alternative surrogate endpoint in patients with lung cancer with EGFR mutations." ESMO Open 3, no. 7 (2018): e000399. http://dx.doi.org/10.1136/esmoopen-2018-000399.
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BackgroundEpidermal growth factor receptor (EGFR) is one of the most common oncogenes in non-small cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitor (TKI) and platinum-doublet chemotherapy (PT) are effective regimens in patients with NSCLC harbouring EGFR mutations. Among these patients, progression-free survival (PFS) has been used as a surrogate endpoint; however, it may not correlate with overall survival (OS) due to crossover. Time to failure of strategy (TFS) has been proposed as an alternative endpoint in advanced colorectal cancer clinical trials where multiple effective therapies are provided either in combination or sequentially. Nevertheless, it remains unclear whether TFS is useful in lung cancer trials.Patients and methodsWe retrospectively reviewed patients with NSCLC harbouring EGFR mutations who chose a treatment strategy consisting of EGFR-TKI and PT as the initial two regimens at the National Cancer Center Hospital. We evaluated the relationship between PFS and OS and between TFS and OS.ResultsBetween May 2005 and April 2015, a total of 374 patients were diagnosed with NSCLC harbouring EGFR mutations. Among them, 158 patients were eligible for analysis. The median PFS, TFS and OS of the patients were 11.2 months (95% CI 9.9 to 12.6), 21.3 months (95% CI 18.6 to 26.2) and 36.6 months (95% CI 32.0 to 41.8), respectively. OS and TFS, but not PFS, were better in patients who received PT then EGFR-TKI compared with those who received the opposite schedule. The non-parametric Spearman’s rank correlation coefficients (r) between PFS and OS and between TFS and OS were 0.54 and 0.85, respectively.ConclusionsThis is the first report describing TFS data among patients with NSCLC with EGFR mutations who received EGFR-TKI and PT as the initial two regimens. TFS was acceptable as a surrogate endpoint for OS. Further validation in clinical trials is needed.
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Broich, Karl. "Outcome measures in clinical trials on medicinal products for the treatment of dementia: a European regulatory perspective." International Psychogeriatrics 19, no. 3 (2007): 509–24. http://dx.doi.org/10.1017/s1041610207005273.
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Based on efficacy and safety data, several drugs have been approved for symptomatic improvement of dementia of the Alzheimer type and one for the symptomatic improvement of dementia associated with Parkinson's disease. However, established treatment effects must be considered as modest. Randomized clinical trials in other subtypes of dementia (e.g. vascular dementia) have not been able to demonstrate clinically relevant symptomatic improvement, nor has it yet been possible to establish disease-modifying effects in any dementia syndrome or its subtypes. Recent progress in basic science and molecular biology of the dementias has now fostered new interest for more efficacious symptomatic treatments as well as for disease-modifying approaches in the degenerative dementias.For regulatory purposes this requires better standardization and refinement of diagnostic criteria, which allow the study of homogeneous disease populations in specialized academic centers as well as in the general community setting. Depending on the disease stages (early versus late, mild to moderate to severe impairment) and disease entities, distinct assessment tools for cognitive, functional and global endpoints should be used or newly developed. The typical design to show symptomatic improvement is a randomized, double-blind, placebo-controlled, parallel group study comparing change in two primary endpoints, one of them reflecting the cognitive domain and the second preferably reflecting the functional domain of impairment. The changes must be robust and clinically meaningful in favor of active treatment versus placebo.If a treatment claim for prevention of the emergence, slowing or stabilizing deterioration is strived for, it has to be shown that the treatment has an impact on the underlying neurobiology and pathophysiology of the process of dementia. Establishing such an effect in a highly variable progressing syndrome is complex and difficult; however, a variety of trial designs has been provided, including baseline designs, survival designs, randomized start or randomized withdrawal designs, with or without incorporation of biomarkers as surrogate endpoints (e.g. magnetic resonance tomography, emission tomography, cerebrospinal fluid markers). To be accepted as a surrogate endpoint such a biomarker ideally should respond to treatment, predict clinical response and be compellingly related to the pathophysiological process of the dementia. However, careful and sufficient validation of proposed biomarkers as a potential surrogate endpoint is a prerequisite for acceptance by regulatory bodies.This review outlines the regulatory requirements for approval of a new medicinal product for symptomatic improvement or disease-modifying effects in patients with dementia, with special emphasis on the importance of validation of the assessment tools and potential surrogate endpoints based on recent experience and discussion regarding anti-dementia drugs in the European framework.
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Rowe, Ian A. "Histological Endpoints for Nonalcoholic Steatohepatitis Trials: Lights and Shadows." Seminars in Liver Disease 40, no. 04 (2020): 339–45. http://dx.doi.org/10.1055/s-0040-1709491.
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AbstractNonalcoholic steatohepatitis (NASH) with liver fibrosis is an increasingly important cause of liver-related morbidity and mortality. A diagnosis of NASH can only be made using liver biopsy. Liver histology also forms the endpoint for the expedited licensing strategies that have been approved by regulators to allow patients with NASH access to treatment before the impact of these on clinical outcomes is known. Validation of these histological surrogate endpoints is critical for the ongoing development of new therapies for NASH. The use of liver biopsy to define both trial entry and endpoints raises questions about the use of treatments for NASH in practice when the effectiveness of treatment will likely depend, at least in part, on the use of histology for patient selection in the real world.
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Yucel, E., M. Lunan, L. Hartley, O. Ahdesmaki, R. Bull, and E. Hawe. "CO90 A Systematic Literature Review of Prognostic Factors and Surrogate Endpoint Analyses in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma." Value in Health 25, no. 12 (2022): S35. http://dx.doi.org/10.1016/j.jval.2022.09.169.
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Pessach, Ilias, Theodoros Spyropoulos, Eleftheria Lamprianidou, and Ioannis Kotsianidis. "MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?" Cancers 14, no. 17 (2022): 4294. http://dx.doi.org/10.3390/cancers14174294.
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Acute myeloid leukemia (AML) is a heterogeneous group of clonal myeloid disorders characterized by intrinsic molecular variability. Pretreatment cytogenetic and mutational profiles only partially inform prognosis in AML, whereas relapse is driven by residual leukemic clones and mere morphological evaluation is insensitive for relapse prediction. Measurable residual disease (MRD), an independent post-diagnostic prognosticator, has recently been introduced by the European Leukemia Net as a new outcome definition. However, MRD techniques are not yet standardized, thus precluding its use as a surrogate endpoint for survival in clinical trials and MRD-guided strategies in real-life clinical practice. AML resistance and relapse involve a complex interplay between clonal and immune cells, which facilitates the evasion of the leukemic clone and which is not taken into account when merely quantifying the residual leukemia. Multiparameter flow cytometry (MFC) offers the possibility of capturing an overall picture of the above interactions at the single cell level and can simultaneously assess the competence of anticancer immune response and the levels of residual clonal cells. In this review, we focus on the current status of MFC-based MRD in diverse AML treatment settings and introduce a novel perspective of combined immune and leukemia cell profiling for MRD assessment in AML.
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Miksad, R., V. Zietemann, R. Mattheucci Gothe, et al. "PCN63 META-ANALYTIC, TRIAL-LEVEL APPROACH TO VALIDATION OF PROGRESSION-FREE SURVIVAL AS A SURROGATE ENDPOINT IN ADVANCED BREAST CANCER." Value in Health 10, no. 6 (2007): A342. http://dx.doi.org/10.1016/s1098-3015(10)65221-7.
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Kok, P. S., W. H. Yoon, I. Marschner, S. J. Lord, M. Friedlander, and C. K. Lee. "Validation of progression-free survival (PFS) as surrogate endpoint in randomised trials of immune checkpoint inhibitors in advanced solid cancers." Annals of Oncology 30 (October 2019): v520. http://dx.doi.org/10.1093/annonc/mdz253.103.
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