Bernhard Wörmann’s research while affiliated with Charité Universitätsmedizin Berlin and other places

Background: We examined four potential challenges for the implementation of the European Union (EU) Regulation 2021/2282 on Health Technology Assessment (EU HTAR): interaction with the European Medicines Agency (EMA), expert input, the interface of European health technology assessment (EU HTA) joint procedures with those within Member States, and the management of conflict of interest. This research aims to explore how to address these challenges in a balanced manner and prioritise key actions for effective collaboration in the context of the EU HTA. Methods: The methodology included a pre-convention survey among relevant stakeholders as well as working groups and the plenary ranking of discussion outcomes at the European Access Academy (EAA) Spring Convention 2024. Results: In the survey, 65.5% of respondents indicated that experts are currently not sufficiently included in the upcoming joint scientific consultations and clinical assessments; only 37.9% suggested that the EU HTA joint procedures would accelerate national appraisal decision-making, and 58.6% believed that the principles of ‘transparency’ and ‘competency’ are balanced in the EU HTA position on conflict of interest. The top priority action points identified in the working groups were the involvement of the best available expertise, the early and inclusive involvement of experts, strengthened early scientific dialogue, and the fostering of the political willingness/financial support of EU Member States to increase capacities. Conclusions: The key topics identified were an approach to conflict of interest that balances transparency obligations and the need for expertise, strengthens the involvement of clinical and patient experts, intensifies early interaction between the EMA and EU HTA, and increases the involvement of the EU Member States.

Introduction To summarize insights generated during the preceding four conventions of the European Access Academy (EAA) regarding the interface of patient organizations and medical societies with the evolving European Union (EU) health technology assessment (HTA) process. Methods In 2022 and 2023 four EAA conventions were held on the EU HTA regulation, focusing on: (i) its relevance for beating cancer; (ii) stakeholder involvement; (iii) recommended preparatory steps to ensure its successful implementation; and (iv) the role of hematology and oncology as a pacemaker for the EU HTA process. Here we summarize insights generated at the four EAA conventions about the integration of patient and clinician insights in the evolving EU HTA process, including joint scientific consultations (JSC) and joint clinical assessments (JCA). Results Throughout the conventions it became clear that the interface of patient associations and clinical societies with the EU HTA process is key for successful implementation of the regulation. All involved stakeholders rely on the principles of evidence-based medicine (EBM), including best internal and external evidence, patient values and expectations, and clinical experience. It was agreed that patient and clinician perspectives on the assessments are needed to balance the technical analysis of best external evidence. While patient input is rather well defined, when and how input from clinical societies is best incorporated during the process remains unclear. Conclusions As stipulated by the EBM triad, systematic involvement of patients and clinicians throughout both JSC and JCA is key to ensuring best outcomes for patients and society as a whole, in line with the objectives of the EU HTA regulation.

Secondary-type mutations (STM) are defined as alterations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 in the recent update of the WHO classification on myeloid neoplasms. The International Consensus Classification (ICC) extends its definition to also include alterations of RUNX1. Patients bearing STMs are considered adverse risk in the absence of other class-defining markers according to the recent update of the European LeukemiaNet (ELN) 2022 recommendations. However, it is unclear if all STMs convey an equally adverse prognostic effect or if individual STMs have a differential prognostic impact. We pooled data on molecular genetics, cytogenetics, and outcomes of 5311 newly diagnosed and intensively treated AML patients from previous randomized multicenter trials of the German SAL (n=1606), the German-Austrian AMLSG (n=1354, dataset from Gerstung et al., Nature Genetics 2017), the German AMLCG (n=1138), the French DATAML (n=1040), and the Czech CELL (n=173). Patients were retrospectively categorized into ELN2022. All analyses were carried out for WHO 2022 definitions (STMWHO) and ICC 2022 definitions (STMICC). We found 1485 (28%) of patients to harbor STMWHO and 1698 patients (32.0%) with STMICC. Patients with STMWHO and STMICC were significantly older than non-STM patients (median 60 vs 53 and 59 vs 52 years, p<0.001) and more frequently male (STMWHO: 62.5% and STMICC: 61.1% male vs 48.3% and 48.1%, p<0.001). STM-bearing patients had significantly higher rates of secondary AML (STMWHO: 19.8% and STMICC: 19.2% vs 6.9% and 6.3%) while de novo AML rates were significantly lower (STMWHO: 75.5% and STMICC: 75.8% vs 87.7% and 88.3%) compared to non-STM patients. Patients with STMs presented with significantly lower white blood cell count as well as significantly lower bone marrow and peripheral blood blast counts. After intensive induction therapy, 65.1% or 65.7% of patients with STMWHO or STMICC achieved complete remission (CR) compared to 77.2% or 77.7% of patients without STM according to either definition (OR 0.55 and p<0.001 for both). To test whether STMs constitute an individual risk group aside from ELN2022 adverse, these groups were separated. Patients with STMs and co-occurring defining favorable or intermediate risk features were assigned to ELN2022 favorable or intermediate risk, respectively. Patients with STM and no other class-defining alterations had longer event-free survival (EFS; STMWHO: 4.7 months, hazard ratio [HR] 1.66, p<0.001; STMICC: 4.9 months. HR 1.69, p<0.001) than ELN2022 adverse risk patients (3.0 months, HR 2.02, p<0.001, and 2.7 months, HR 2.12, p<0.001, respectively), longer relapse-free survival (RFS; STMWHO: 12.6 months, HR 1.53, p<0.001, STMICC: 11.9 months, HR 1.60, p<0.001 vs 8.0 months, HR 1.91, p<0.001 and 7.4 months, HR 1.93, p<0.01, respectively), and longer overall survival (OS; STMWHO: 14.6 months, HR 1.64, p<0.01 and STMICC: 14.7 months, HR 1.68, p<0.01 vs 9.5 months, HR 2.09, p<0.001 and 8.3 months, HR 2.22, p<0.001, respectively). The odds of achieving CR were significantly decreased for alterations in ASXL1, BCOR, SF3B1, SRSF2, STAG2, U2AF1, or RUNX1 compared to wildtype (univariable OR range: 0.38-0.68; BCOR p=0.003; all other p<0.001), with no significant differences for EZH2 (OR: 0.87, p=0.387) or ZRSR2 (OR: 0.96, p=0.882). Median EFS was significantly reduced for patients harboring alterations in ASXL1, BCOR, SF3B1, SRSF2, STAG2, U2AF1, or RUNX1 (HR range: 1.17-1.79; STAG2 p=0.017, all other p<0.001) while there was no difference for EZH2 (HR: 1.11, p=0.167) or ZRSR2 (HR: 1.17, p=0.232) compared to wildtype patients. Significantly reduced median RFS was found for patients with altered ASXL1, BCOR, SF3B1, SRSF2, U2AF1, and RUNX1 (HR range: 1.28-1.88, BCOR p=0.007, SF3B1 p=0.005, all other p<0.001) while EZH2, STAG2, and ZRSR2 showed no significant differences (HR range: 0.93-1.17). Finally, OS was significantly reduced for patients harboring alterations in ASXL1, BCOR, SF3B1, SRSF2, U2AF1, and RUNX1 (HR range: 1.26-1.87, BCOR p=0.002, all other p<0.001) again with no difference for alterations of EZH2, STAG2, and ZRSR2 (HR range: 1.16-1.28). Our analysis highlights that STMs represent an unfavorable risk level between the ELN2022 intermediate and adverse categories while contrasts between individual STMs exist, as not all alterations convey the same degree of adverse prognostic impact.

Assignment of patients diagnosed with acute myeloid leukemia (AML) to the 2022 European LeukemiaNet (ELN) favorable genetic risk group has important clinical implications, as allogeneic stem cell transplantation in first complete remission (CR) is not advised due to a relatively good outcome of patients receiving chemotherapy alone and transplant-associated mortality. However, not all favorable genetic risk patients experience long-term relapse-free survival (RFS), making recognition of patients who would most likely be cured of high importance. We analyzed 297 patients aged <60 years with de novo AML classified as 2022 ELN favorable genetic risk who achieved a CR and had RNA sequencing (RNA-seq) and gene mutation data from diagnostic samples available (Alliance trial A152010). To identify prognostically relevant transcripts that can distinguish patients cured from patients susceptible to lower or higher risk of relapse or death, we fit a regularized mixture cure model (MCM) where RNA-seq expression values were our candidate covariates. To validate the identified transcripts, we analyzed 75 patients with de novo AML aged <60 years included in the 2022 ELN favorable genetic risk group who achieved a CR in an independent test set from Gene Expression Omnibus (GSE37642). Our MCM identified 145 transcripts associated with cure or long-term RFS and 149 transcripts associated with latency or shorter-term time to relapse. The area under the curve and C-statistic were, respectively, 0.946 and 0.856 for our training set and 0.877 and 0.857 for our test set. Our results suggest that the favorable risk group includes distinct transcriptionally defined subgroups with different biological properties, which may be useful for refining this genetic risk category.

This article briefly summarizes clinically relevant new aspects of the recently published German, Austrian and Swiss onkopedia guideline for the treatment of locally advanced rectal cancer. Main aspects comprise (i) the use of total neoadjuvant therapy (TNT) for rectal cancers with high risk features, (ii) treatment with neoadjuvant chemotherapy for patient with a low risk for local recurrence, (iii) immunotherapy using dostarlimab in patients with MSI high /dMMR rectal cancer as well as (iv) intended organ preservation as a treatment goal. The availability of several evidence-based treatment options requires intensive discussion within the multidisciplinary team as well as dedicated information for patients about treatment goals, options and risks of individual treatment approaches.

Background: This work aimed to determine the role and action points for the involvement of medical societies in the European Health Technology Assessment (EU HTA) Methods: An online pre-convention survey was developed addressing four areas related to the EU HTA: (i) medical societies’ role; (ii) role of clinical guidelines; (iii) interface with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS); and (iv) approaching ‘best-available evidence’ (BAE). A descriptive analysis of questionnaire outcomes was conducted to inform the European Access Academy (EAA) Fall Convention 2023. Within the working groups (WGs), action points were identified and prioritised. Results: A total of 57 experts from 15 countries responded to the survey. The WGs were attended by (i) 11, (ii) 10, (iii) 12, and (iv) 12 experts, respectively, representing a variety of national backgrounds and stakeholder profiles. The most relevant action points identified were as follows: (i) incorporation of clinical context into population, intervention, comparator, outcomes (PICO) schemes, (ii) timely provision of up-to-date therapeutic guidelines, (iii) ensuring the inclusion of MCBS insights into the EU HTA process, and (iv) considering randomized controlled trials (RCTs) as the gold standard and leveraging regulatory insights if development programs only include single-arm trials. Conclusions: The involvement of medical societies is a critical success factor for the EU HTA. The identified key action points foster the involvement of patient associations and medical societies.

In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by 1. the urgency relevant to avoid or reduce harm; 2. the likelihood of success of the diagnostic or therapeutic measure advised; and 3. the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin and other social characteristics, such as social or insurance status, as well as the vehemence of a patient’s treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for 1. diagnostic procedures, 2. surgical procedures for cancer, and 3. systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms).