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Institute
Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Background
The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).
Methods
Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.
Results
Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).
Conclusion
In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.
Background
Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed.
Methods
We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM.
Results
AML patients with EM presented with significantly higher counts of white blood cells (p < 0.0001), peripheral blood blasts (p < 0.0001), bone marrow blasts (p = 0.019), and LDH (p < 0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p < 0.001), FLT3-ITD (OR: 1.72, p < 0.001) and PTPN11 (OR: 2.46, p < 0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p = 0.004), and had a higher early death rate (OR: 2.23, p = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p < 0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p < 0.001, and HR: 2.05, p = 0.044, respectively) and overall survival (HR: 2.48, p = 0.026, and HR: 2.63, p = 0.008, respectively).
Conclusion
Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM.
In qualitative research, results often emerge through an analysis process called coding. A common measure of validity of theories built through qualitative research is the agreement between different people coding the same materials. High intercoder agreement indicates that the findings are derived from the data as opposed to being relative results based on the original researcher's bias. However, measuring such intercoder agreement incurs the high cost of having additional researchers perform seemingly redundant work. In this paper we present first results on a novel method of using students for validating theories. We find that intercoder agreement between a large number of students is almost as good as the intercoder agreement between two professionals working on the same materials.
The Code System of a Systematic Literature Review on Pre-Requirements Specification Traceability
(2020)
Tracing requirements back to their origin is important to understand the context and to identify all potential concerns or conflicts in the genesis of the requirements. The so-called pre-requirements specification (pre-RS) traceability is part of requirements traceability (RT) and is recognized as an important factor for long-term project success. Different approaches have been developed to connect requirements and their origin, but still, there is no general established solution. Mostly it is seen as an effort without significant benefits leading to resistance towards its implementation. To guide future research, a comprehensive understanding of the use cases, benefits, challenges, and existing approaches encountered is vital. However, the landscape of the scientific literature on this field remains somewhat fragmented, with pre-RS traceability often only considered in the periphery. We, therefore, conducted a systematic literature review, which identified 67 relevant papers. The literature was coded using qualitative data analysis (QDA) methods. In this technical report, we present the whole resulting code system of the QDA and describe the relationships between the identified themes, focusing on the relevance, problems, solutions, and techniques of pre-RS traceability.
Traceability is an important quality aspect in modern software development.
It facilitates the documentation of decisions and helps identifying conflicts regarding the conformity of one artifact to another. We propose a new approach to requirements engineering that utilizes qualitative research methods, which have been well established in the domain of social science. Our approach integrates traceability between the original documentation and the requirements specification and the domain model and glossary and supports adaptability to change.
Background: In the ‘Arimidex’, Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a significantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100- month analysis of the ATAC trial from the perspective of the German public health insurance. Patients and Methods: A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. Results: Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($ 30,717) per QALY gained. Conclusions: This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen.
The creation of domain models from qualitative input relies heavily on experience. An uncodified ad-hoc modeling process is still common and leads to poor documentation of the requirements analysis.
In this thesis, we present a novel method for domain analysis based on qualitative data analysis (QDA). The method helps identifying inconsistencies, ensures a high degree of completeness, and inherently provides traceability from analysis results back to stakeholder input.
In our approach, the QDAcity-RE method, the research process of theory building facilitates domain analysis within the requirements elicitation phase of a software development project.
We show how an iterative process of concurrent data collection and analysis can be applied to requirements engineering (RE), including open, axial, and selective coding of qualitative data.
The traceability of domain model elements back to original statements by stakeholders, generated by our method, does not have to be created and maintained separately after the fact. The traces are documented in an analysis artifact called the code system, which evolves iteratively with the analysis process. The code system can act as a universal model from which a variety of artifacts can be derived, describing both behavioral and structural aspects. This thesis focuses on the creation of conceptual domain models using QDAcity-RE, but peripherally also demonstrates this capability through the generation of behavioral models and a software requirements specification.
We applied and evaluated our method for domain modeling in four exploratory projects in the domains of medical imaging diagnostics, railway systems, HR development, and qualitative research.
We show that by applying QDA to domain analysis, structural elements and relationships needed to derive a UML class diagram can be extracted from a code system based on interviews with domain experts. Constant comparison and theoretical sampling assist in integrating differing domain descriptions into an abstract model.
While the analysis process still requires interpretations and modeling decisions, our method provides more guidance than existing domain analysis approaches and a thorough documentation of these decisions. In addition, codes and memos ensure traceability between the original data and the derived model and assist in connecting several RE artifacts, ensuring a high degree of inter-model consistency.
We validated our claim that QDAcity-RE helps an analyst gain a deeper understanding of a problem domain through a controlled experiment.
FLT3-ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alterations, there is only limited information on molecular and clinical associations. To evaluate the prognostic impact of non-ITD mutations in the FLT3 JMD region, we analyzed a large cohort of 1,539 adult AML patients treated in different protocols of the Study Alliance Leukemia, using next-generation sequencing. Non-ITD point mutations and deletions within the FLT3 JMD were identified with a prevalence of ~1.23% (n = 19). Both FLT3-ITD and non-ITD mutations were associated with a higher rate of NPM1 (42%–61%; p < 0.001) and DNMT3A mutations (37%–43%; p < 0.001), as well as an increased percentage of peripheral blood (54%–65%) and bone marrow blast cells (74%; p < 0.001), compared to FLT3-wild-type patients. Most significantly, AML patients with FLT3 non-ITD mutations had a higher rate of concomitant KMT2A-PTD mutations (37.5%; p < 0.001) as compared to FLT3-ITD (7%) or FLT3-wild-type cases (4.5%). In a multivariable analysis, FLT3 non-ITD mutations were not an independent prognostic factor. However, patients with dual FLT3 non-ITD and KMT2A-PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML.
Background
Overall survival remains poor in older patients with acute myeloid leukemia (AML) with less than 10% being alive after 5 years. In recent studies, a significant improvement in event-free, relapse-free and overall survival was shown by adding gemtuzumab ozogamicin (GO), a humanized antibody-drug conjugate directed against CD33, to intensive induction therapy once or in a sequential dosing schedule. Glasdegib, the small-molecule inhibitor of smoothened (SMO), also showed improved overall survival in patients not eligible for intensive chemotherapy when combined with low-dose cytarabine compared to low-dose cytarabine alone. These findings warrant further investigations in the phase III GnG trial.
Methods/Design
This is a randomized phase III trial with measurable residual disease (MRD) after induction therapy and event-free survival (EFS) as primary endpoints. The two research questions are addressed in a 2 by 2 factorial design. Patients age 60 years and older are upfront randomized 1:1 in one of the two induction arms: GO administered to intensive induction therapy on days 1,4, and 7 versus GO administered once on day 1 (GO-147 versus GO-1), and double-blinded 1:1 in one of the subsequent treatment arms glasdegib vs. placebo as adjunct to consolidation therapy and as single-agent maintenance therapy for six months. Chemotherapy backbone for induction therapy consists of standard 7 + 3 schedule with cytarabine 200 mg/m2 continuously days 1 to 7, daunorubicin 60 mg/m2 days 1, 2, and 3 and high-dose cytarabine (1 g/m2, bi-daily, days 1, 2, and 3) for consolidation therapy. Addressing two primary endpoints, MRD-negativity after induction therapy and event-free survival (EFS), 252 evaluable patients are needed to reject each of the two null hypotheses at a two-sided significance level of 2.5% with a power of at least 85%.
Ethics and dissemination
Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.
Trial status
Protocol version: 1st version 20.10.2020, no amendments yet. Study initiation on February 16, 2021. First patient was recruited on April 1st.
Trial registration
ClinicalTrials.govNCT04093505; EudraCT 2019-003913-32. Registered on October 30, 2018.
Using qualitative data analysis (QDA) to perform domain analysis and modeling has shown great promise. Yet, the evaluation of such approaches has been limited to single-case case studies. While these exploratory cases are valuable for an initial assessment, the evaluation of the efficacy of QDA to solve the suggested problems is restricted by the common single-case case study research design. Using our own method, called QDAcity-RE, as the example, we present an in-depth empirical evaluation of employing qualitative data analysis for domain modeling using a controlled experiment design. Our controlled experiment shows that the QDA-based method leads to a deeper and richer set of domain concepts discovered from the data, while also being more time efficient than the control group using a comparable non-QDA-based method with the same level of traceability.