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In a randomized phase II trial (AMLSG 14-09, NCT00867672) of elderly, newly diagnosed AML patients, ATRA combined with decitabine (DEC) significantly improved the overall response rate (ORR) and survival also in patients with adverse-risk genetics, without adding toxicity. We performed a post hoc analysis to determine the predictive impact of TP53 status. Despite a nominally higher ORR, the clinically meaningful survival benefit when adding ATRA to DEC was diminished, but not completely negated, in TP53-mutated patients. Indeed, 2 out of 14 TP53-mutated patients (14%) randomized to a DEC + ATRA-containing regimen lived for > 36 months. Further studies of ATRA combined with hypomethylating agents appear warranted in non-M3 AML patients ineligible for HMA/venetoclax therapy. Trial Registration: ClinicalTrials.gov identifier: NCT00867672., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Objectives: Due to disease- or therapy-associated immunosuppression, oncological patients suffer from significantly higher morbidity and mortality due to infections transmitted by respiratory pathogens such as Streptococcus pneumoniae and influenza virus. Although the German Standing Committee on Vaccination (STIKO) provides specific recommendations for vaccination against these pathogens, there is no data on vaccination rates in this high-risk population., Methods: Data from the interventional EVO study were analyzed to provide information on vaccination rates against Streptococcus pneumoniae and influenza virus in oncological patients. Numbers presented in this publication summarize baseline and follow-up data of the control group; thus, data were not influenced by the intervention., Results: Data of 370 patients were analyzed; 20.5% of patients were treated for hematological malignancies and 79.5% for solid cancer. 28.1% of patients had received vaccination against influenza and 32.2% against Streptococcus pneumoniae; for the latter only 7.3% according recommendations. While vaccination rates where even lower for patients with thoracic carcinoma (influenza 26.7% and Streptococcus pneumoniae 6.0% according to STIKO recommendations), rates in patients with multiple myeloma were remarkably higher (39.0% and 14.6%)., Conclusions: Despite strong recommendations to vaccinate and the clear clinical need to prevent infections in the vulnerable group of oncological patients, only the minority was vaccinated against Streptococcus pneumoniae or influenza, underlining the urgent need for better vaccination strategies in this high-risk population., Competing Interests: Declarations. Ethics approval: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Brandenburg Medical School as part of a broader study context (protocol code E-01–20190123, date of approval 10 April 2019). Informed consent: Informed consent was obtained from all subjects involved in the study. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

DNA-hypomethylating agents (HMAs) induce notable remission rates in AML/MDS patients with TP53 mutations; however, secondary resistance often develops rapidly. In the DECIDER trial (NCT00867672), elderly AML patients (also those with adverse genetics) randomized to all-trans retinoic acid (ATRA) added to decitabine (DEC) attained significantly delayed time-to-resistance. An 82-year-old patient with a non-disruptive, in-frame TP53 mutation (p.Cys238_Asn239delinsTyr, VAF 90%) and complex-monosomal karyotype attained a complete hematologic and cytogenetic remission with DEC + ATRA, with 3.7 years survival after 30 treatment cycles that were well-tolerated. Further HMA + ATRA studies appear warranted in AML/MDS patients of different genetic risk groups ineligible for more intensive treatment.Trial registration: This trial was registered at ClinicalTrials.gov identifier: NCT00867672., (© 2024. The Author(s).)

Introduction: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses., Materials and Methods: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo)., Results: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy., Discussion: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy., Clinicaltrials: gov: NCT03416244., Competing Interests: Declaration of Competing Interest NMB reports research funding and receipt of equipment from Deutsche Forschungsgemeinschaft. RDH reports advisory for Amgen, Astra Zeneca, Bristol Myers Squibb, Boehringer, Daichi, Lilly, Merck, MSD, Pierre Fabre, Roche, and Servier; honoraria for lectures and presentations from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier; and consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier. AV reports consultancy and advisory role for AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio and Terumo. MdW reports research funding from Pfizer, Abbvie, Novartis, Astellas, Bristol Myers Squibb, AstraZeneca and MorphoSys; speaker's honoraria from AstraZeneca and Janssen; travel or accommodation expenses from Astellas and Janssen. RJ reports consulting fees from Roche and Bayer; payments for lectures and presentations from Dr. Falk Pharma and Bristol Myers Squibb; for writing of manuscripts from Boston Scientific and Springer Nature; advisory for Heidelberg University Hospital; and leading the Endoscopy section of the German Society of Gastroenterology. GS reports consulting fees from Servier, Pharmacosmos, Bristol Myers Squibb, Amgen and travel support from Daichi-Sankyo. PTP reports consulting fees from Bristol Myers Squibb, AstraZeneca, and MSD. TL is Scientific Head at CROLLL GmbH. HB is an employee of a commercial provider of clinical statistics and programming services (Staburo GmbH, Munich). MPE reports funding for conducting the trial from AIO-Studien-gGmbH which is the regulatory sponsor of the trial, and advisory for Bristol Myers Squibb. NH reports advisory for Bristol Myers Squibb. All remaining authors declare no conflicts of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles., Methods: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m 2 intravenously on days 1-3), doxorubicin (35 mg/m 2 intravenously on day 1), and cyclophosphamide (1250 mg/m 2 intravenously on day 1), and standard doses of bleomycin (10 mg/m 2 intravenously on day 8), vincristine (1·4 mg/m 2 intravenously on day 8), procarbazine (100 mg/m 2 orally on days 1-7), and prednisone (40 mg/m 2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503)., Findings: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively., Interpretation: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma., Funding: Takeda Oncology., Competing Interests: Declaration of interests PB reports consulting fees from Takeda, BMS, Roche, Amgen, Novartis, Celgene, Miltenyi Biotech, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, Novartis, BMS, Roche, MSD, Celgene, Miltenyi Biotech, Gilead, and AbbVie; and funding for scientific research from Takeda Oncology, MSD, and Novartis. JF reports funding and consulting fees from Takeda Oncology and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology and Roche Pharma. RG reports consulting fees from Celgene, Novartis, Roche, Takeda, AbbVie, Astra Zeneca, MSD, Merck, Gilead, Daiichi Sanko, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Sanofi; support for attending meetings or travel from Roche, Amgen, Janssen, Astra Zeneca, Novartis, BMS, AbbVie, and Daiichi Sankyo; participating on a data safety monitoring board or advisory board for Celgene, Novartis, Roche, BMS, Takeda, AbbVie, Astra Zeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, and Sanofi; and stock or stock options from Novo Nordisk and Lilly. MHe reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AH reports payment for speakers bureau, funding, and travel support from, and participation on an advisory board for Takeda. FK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and support for attending meetings or travel from Takeda. MHä reports consulting fees from Pfizer, Incyte, Roche, Amgen, Sanofi/Aventis, Sobi, Kite/Gilead, Janssen, and BMS and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Sobi, Novartis, Kite/Gilead, Falk Foundation, and BMS. UN reports consulting fees for the institution from Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript, writing or educational events for the institution from Celgene (BMS), Novartis, Takeda, and Gilead; support to the institution for attending meetings or travel from Janssen, Roche, Gilead, and Takeda; and participating on a data safety monitoring board or advisory board for Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, BeiGene, Kyowa Kiin, Gileag, and Pierre Fabre. JM reports consulting fees from MSD. AZi reports payment for presentations from Novartis, Oncopeptides, Takeda, Incyte, and Roche and travel support from Oncopeptides, Roche, and Novartis. AF reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. AV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, BMS, and AbbVie; support for attending meetings or travel from Janssen, Kite/Gilead, BMS, and AbbVie; and participation on a data safety monitoring board or advisory board from Roche, BMS, AbbVie, and Kite/Gilead. SS reports travelling support from AbbVie and Jazz and reports support for attending meetings or travel from and having a leadership or fiduciary role in another board, society, committee or advocacy group (paid or unpaid) with Pfizer, Amgen, and Novartis. VV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda and participation on an advisory board for Takeda and MSD. AK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Celgene, AbbVie, Sobi, BMS, and Takeda and support for attending meetings or travel from AbbVie, BeiGene, Sobi, Takeda, EUSA Pharma, Novartis, and Alexion. KT-G reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda. PK reports travel support from Roche Pharmaceuticals and Takeda. BvT reports institutional grants or contracts from Esteve, Merck Sharp & Dohme, Novartis, and Takeda; consulting fees from Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Roche, Sobi, and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Lilly, Merck Sharp & Dohme, Novartis, Roche, and Takeda; support for attending meetings or travel from AbbVie, AstraZeneca, Gilead, Kite, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis; payment from Takeda and Regeneron (INSIGHTFUL study); payment to institution from the Olympia 3 study; and participation on a data safety monitoring board or advisory board for Takeda and Regeneron. SB reports consulting fees from Galapagos; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events and consultation from Takeda; support for attending meetings or travel from Takeda; having a leadership role in another board, society, committee, or advocacy group (paid or unpaid), and holding stock or stock options for Liqomics. KB reports funding and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda Oncology. MF reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Celgene, BMS, Takeda, and Janssen. AZo reports Takeda stocks and being an employee of Takeda Oncology. SK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, payment for expert testimony, and support for attending meetings or travel from, and participating on a data safety monitoring board or advisory board for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy., Patients and Methods: The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11., Results: The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed., Conclusion: The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm., (© 2024. The Author(s).)

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47-1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29-0.79) and without previous ASCT (aHR 0.52, 0.28-0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344., (© 2024. The Author(s).)

Purpose: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity., Methods: This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity (<10 -5 , next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS)., Results: Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm., Conclusion: Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Introduction: In patients with a clinical indication for autologous hematopoietic stem cell transplantation (ASCT), sufficient mobilization of CD34 + precursor cells into peripheral blood is essential to ensure adequate hematopoietic stem cell (HSC) collection prior to intensive therapy. However, with standard granulocyte-colony stimulating factor (G-CSF)-based mobilization schemes, an important minority of patients fail to mobilize sufficient (e.g., >10/µL) CD34 + cell counts into the peripheral blood and are considered as poor mobilizers (PM). Because failure to achieve sufficient CD34 + cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34 + mobilization in PM patients., Methods: The German non-interventional, multicenter, open-label, prospective OPTIMOB study evaluated HSC mobilization strategies prior to planned ASCT in adult patients with hematologic malignancies (lymphomas or multiple myeloma [MM]) focusing on PM patients. PM patients were defined as follows: (1) never achieving ≥20 CD34 + cells/µL before 1st apheresis, (2) receiving PLX at any timepoint of mobilization, (3) their initially planned stem cell yield had to be reduced, or (4) they had not received apheresis due to low CD34 + count in peripheral blood., Results: 168 of 475 MM patients (35%) participating in the OPTIMOB study were classified as PM, and 155 of them (92%) received PLX (PM+PLX) during the study. PM patients were 40-78 years old, slightly more often male ( n = 97, 58%), mostly newly diagnosed ( n = 146, 87%) and received highly individualized previous treatments. Ninety-four of the PMs underwent chemotherapy mobilization (65%), and 51 patients (35%) received steady-state mobilization with G-CSF only during 1st mobilization attempt. 92% of the total PM population ( n = 155) underwent apheresis, 78% of them ( n = 117) achieved >2.0 × 10 6 CD34 + cells/kg body weight on the 1st day of apheresis. PM+PLX had a higher median total collection result than those PM patients without PLX support (7.2 vs. 5.7 × 10 6 CD34 + cells/kg body weight). In total, ASCT was performed in 136 PM+PLX (88%) versus 8 PM-PLX patients (62%)., Conclusion: The OPTIMOB study showed that a considerable proportion of adult MM patients in Germany are PMs. Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs., Competing Interests: M.B. received honoraria for advisory board and consultancy activities from Bristol-Myers Squibb, Sanofi-Aventis Deutschland GmbH, and GlaxoSmithKline GmbH & Co. KG; research funding from Bristol-Myers Squibb (Celgene), Otsuka Pharmaceuticals, Sanofi, Chugai Pharma, AbbVie, AMGEN, and Janssen; and owns shares from AbbVie. K.K. received research funding from Bristol-Myers Squibb and Sanofi-Aventis Deutschland GmbH. C.T.S. received honoraria from Sanofi. M.G. (Matthias Grube) received honoraria from Sanofi, Janssen, and Bayer. V.V. received honoraria from Sanofi, Bristol-Myers Squibb, Novartis, Amgen, and Janssen. D.W. received honoraria for advisory board activities and travel support from Sanofi. A.B. received honoraria from Incyte and AOP Orphan and scientific support from AOP Orphan. M.S.H. received honoraria for consultancy activities from Celgene GmbH, Amgen GmbH, Kite/Pharma Gilead, Sanofi-Aventis Deutschland GmbH, GlaxoSmithKline GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KG, Shionogi GmbH, and Stemline Therapeutics (no individual payment) and financial support of educational meetings from Janssen-Cilag GmbH, Takeda Pharma Vertrieb GmbH & Co. KG, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, Vifor Pharma Deutschland GmbH, and Celgene GmbH (no individual payment). Additionally, M.S.H. participated in different clinical trials supported by the industry (including the OPTIMOB study). C. K. (Christoph Kimmich) received honoraria from Amgen, Janssen, Kite/Pharma Gilead, Takeda, GlaxoSmithKline GmbH & Co., and Sanofi-Aventis Deutschland GmbH, as well as travel support from Janssen and Kite/Pharma Gilead. M.H. received lecture fees from Amgen, AstraZeneca, Eusa Pharma, Celgene, Janssen, Jazz Pharma, and Takeda, and served on advisory boards of Amgen, Eusa Pharma, Janssen, and Sanofi. C.K. (Christian Kunz) received honoraria for advisory board activities from AbbVie, Sanofi, Bristol-Myers Squibb, and Amgen, as well as financial support for congress participation from AbbVie, Amgen, and Bristol-Meyer Squibb. C.K. (Cyrus Khandanpour) received honoraria and research funding from Sanofi, Bristol-Myers Squibb, AstraZeneca, Novartis, Amgen, and Janssen. M.W. received honoraria for lectures from AstraZeneca, Novartis, Ispen, Roche, Janssen, Sanofi, Medac, Takeda, and Pierre Fabre; travel support from AstraZeneca, AbbVie, and Pfizer; and research funding from AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Janssen, Takeda, MSD, Boehringer, Pierre Fabre, Amgen, Genzyme, and MorphoSys. U.H. received honoraria from Sanofi and Amgen. R.N. received honoraria for consultancy activities from AvenCell (formerly Cellex Patient Treatment GmbH), Simon Kucher & Partners Strategy & Marketing Consultants GmbH, and Takeda; honoraria for advisory board activities from Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, Oncopeptides, Bristol-Myers Squibb (Celgene), Janssen, Gilead, and Amgen; honoraria for lectures from Forum Medizin Fortbildung (FOMF) and Bildungsinstitut für Gesundheitsberufe Südwestfalen in Siegen (BIGS) GmbH; and honoraria for authorship from Elsevier. C.W.S. received honoraria from Bristol-Myers Squibb, Celgene, Daiichi Sankyo, GILEAD, Hexal, Incyte, Janssen, Lilly, MSD, Merck Serono, Miltenyi Biotec, Novartis, Pfizer, Roche, and Takeda. H.J.T. received honoraria from Sanofi, Bristol-Myers Squibb, and Takeda. F.B. and M.E. are employed by Sanofi-Aventis Deutschland GmbH and may hold stock and/or stock options in the company. N.K. received honoraria and research funding from Sanofi, Bristol-Myers Squibb, Neovii, Novartis, Amgen, and Riemser. A.K., K.M., A.S., M.G. (Martin Görner), F.H., H.A.D., A.R., B.M., and M.K. have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Successful mobilization and collection of peripheral hematopoietic stem cells (HSCs) are necessary for lymphoma patients eligible for myeloablative chemotherapy with subsequent autologous stem cell transplantation (ASCT). Albeit G-CSF alone or combined with chemotherapy is well-established methods for HSC mobilization, up to 40% of the patients fail to mobilize (poor mobilizer, PM). Plerixafor (PLX) is commonly used in PM patients resulting in increased migration of HSCs into peripheral blood and thus improves the collection outcome., Methods: The prospective, multicenter, open-label, non-interventional OPTIMOB study assessed mobilization and collection parameter of patients with lymphoma or multiple myeloma to get deep insights in the treatment of those patients in clinical routine focusing on PM patients. PM was defined as follows: (1) no achievement of ≥20 CD34 + progenitor cells/µL before first apheresis, (2) PLX administration at any time point during the observational period, (3) reduction of the initially planned CD34 + progenitor cell yield as necessity due to failed mobilization or HSC collection, and (4) no performance of apheresis due to low CD34 + progenitor level. Primary objective of the study was to assess mobilization success by the proportion of PM patients achieving >2 × 10 6 CD34 + progenitor cells/kg body weight on the first day of apheresis. Here, the data of the lymphoma cohort are presented., Results: Out of 238 patients with lymphoma documented in the study, 32% were classified as PM. 87% of them received PLX. Demographic data revealed no obvious differences between PM and good mobilizing (GM) patients. All patients were treated highly individualized prior to mobilization. Majority of all PM patients were able to undergo apheresis (95%) and reached their individual requested CD34 + progenitor cell target (72%). 57% of the PM patients achieved >2.0 × 10 6 CD34 + progenitor cells/kg body weight on day 1 of apheresis and nearby 70% of them underwent ASCT. Median time to engraftment was similar in PM and GM patients of the lymphoma cohort., Conclusions: Majority of PM patients with lymphoma were successfully mobilized and underwent ASCT. Most of them received PLX during the study., Competing Interests: K.K. received research funding from Bristol Myers Squibb and Sanofi-Aventis Deutschland GmbH. M.B. received honoraria for advisory board and consultancy activities from Bristol Myers Squibb, Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, research funding from Bristol Myers Squibb (Celgene), Otsuka Pharmaceuticals, Sanofi, Chugai Pharma, Abbvie, AMGEN, and Janssen, and owns shares from Abbvie. S.S. received honoraria and research funding from Sanofi-Aventis Deutschland GmbH, Bristol Meyers Squibb, Amgen, and Janssen. C.T.-S. received honoraria from Sanofi. M.G. (Matthias Grube) received honoraria from Sanofi, Janssen, and Bayer. V.V. received honoraria from Sanofi, Bristol Myers Squibb, Novartis, Amgen, and Janssen. D.W. received honoraria for advisory board activities and travel support from Sanofi. A.B. received honoraria from Incyte and AOP Orphan and scientific support from AOP Orphan. M.S.-H. received honoraria for consultancy activities from Celgene GmbH, Amgen GmbH, Kite/Pharma Gilead, Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, Bristol Myers Squibb GmbH & Co. KG, Shionogi GmbH, Stemline Therapeutics (no individual payment) and financial support of educational meetings from Janssen-Cilag GmbH, Takeda Pharma Vertrieb GmbH & Co. KG, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, Vifor Pharma Deutschland GmbH, and Celgene GmbH (no individual payment). Additionally, M.S.-H. participated in different clinical trials supported by the industry (including the OPTIMOB study). C.K. (Christoph Kimmich) received honoraria from Amgen, Janssen, Kite/Pharma Gilead, Takeda, Glaxo Smith Kline GmbH & Co, and Sanofi-Aventis Deutschland GmbH as well as travel support from Janssen and Kite/Pharma Gilead. M.H. received lecture fees by Amgen, AstraZeneca, EusaPharma, Celgene, Janssen, Jazz Pharma, and Takeda, and served on advisory boards of Amgen, EusaPharma, Janssen, and Sanofi. C.K. (Christian Kunz) received honoraria for advisory board activities from Abbvie, Sanofi, Bristol Meyer Squibb, and Amgen as well as financial support for congress participation from Abbvie, Amgen, and Bristol Meyer Squibb. C.K. (Cyrus Khandanpour) received honoraria and research funding from Sanofi, Bristol Myers Squibb, AstraZeneca, Novartis, Amgen, and Janssen. M.W. received honoraria for lectures from AstraZeneca, Novartis, Ispen, Roche, Janssen, Sanofi, Medac, Takeda, and Pierre Fabre, travel support from AstraZeneca, Abbvie, and Pfizer, and research funding from AstraZeneca, Bristol Meyer Squibb, Novartis, Phizer, Roche, Janssen, Takeda, MSD; Boehringer, Pierre Fabre, Amgen, Genzyme, and MorphoSys. U.H. received honoraria from Sanofi and Amgen. R.N. received honoraria for consultancy activities from AvenCell (formerly Cellex Patient Treatment GmbH), Simon Kucher and Partners Strategy and Marketing Consultants GmbH, and Takeda, honoraria for advisory board activities from Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, Oncopeptides, Bristol Myers Squibb (Celgene), Janssen, Gilead, Amgen, honoraria for lectures from Forum Medizin Fortbildung (FOMF), Bildungsinstitut für Gesundheitsberufe Südwestfalen in Siegen (BIGS) GmbH, and honoraria for authorship from Elsevier. C.W.S. received honoraria from Bristol Myers Squibb, Celgene, Daiichi Sankyo, GILEAD, Hexal, Incyte, Janssen, Lilly, MSD, Merck Serono, Miltenyi Biotec, Novartis, Pfizer, Roche, and Takeda. H.J.T. received honoraria from Sanofi, Bristol Meyer Squibb, and Takeda. F.B. and M.E. are Employed by Sanofi-Aventis Deutschland GmbH and May Hold Stock and/or Stock Options in the Company. N.K. received honoraria and research funding from Sanofi, Bristol Myers Squibb, Neovii, Novartis, Amgen, and Riemser. A.K., K.M., A.S., M.G. (Martin Görner), F.H., H.A.D., A.R., B.M., and M.K. have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Guidelines recommend a structured symptom screening (SC) for especially advanced cancer patients (CPs). The aim of this multicenter German prospective quality assurance project KeSBa (Kennzahl Symptom- und Belastungserfassung) was to gain knowledge on SC procedures in Oncology Centers (OCs) for advanced cancer patients and a first impression on the consequences of SC., Methods: The KeSBa project consisted of three phases: pilot, 3 months screening and feedback phase. Participating OCs decided to use either the Minimal Documentation System (MIDOS) or the Integrated Palliative care Outcome Scale (IPOS) and defined the cutoff values for positive screening results., Results: Out of 172 certified German OCs, 40 (23%) participated in the KeSBa pilot phase, 29 (16.8%) in the 3 months screening phase using MIDOS (n = 18, 58.6%) or IPOS (n = 11, 41.3%) and in the feedback round. 25/29 performed paper-based screening (86.2%). 2.963 CPs were screened. Results were documented for 1255 (42.2%, SC +) positive and 874 (29.5%, SC-) negative screenings depending on the center´s schedules: 452 SC + CPs (28.4%) and 42 SC- CPs (2.6%) had contact to specialized palliative care or other supportive specialist teams afterwards, 458 SC + CPs (28.8%) and 605 SC- CPs (38.1%) remained in standard oncology care. In the feedback round missing resources (personal and IT) and improved communication were mentioned most often., Conclusion: Routine SC is feasible in advanced CPs treated in OCs but associated with considerable workload. In 42.2% of CPs SC was classified as positive, indicating the need of further diagnostics or professional judgment. SC requires staff and IT resources., (© 2023. The Author(s).)

Purpose: This study aimed to find out more about factors that hinder physicians' careers, especially with regard to gender differences, and which future working conditions they would prefer., Methods: In an online survey, members of the professional societies of Hematology and Oncology in Germany, Austria and Switzerland were asked to rate factors that might hinder or facilitate their professional career. Data analysis included χ 2 -tests, t tests and analyses of variance., Results: 469 physicians participated (61% female, response rate 9.1%). 40% of the participants experience a lack of compatibility between family life and career. Female physicians with children living in their household especially feel restricted in their professional development. The most preferred conditions for improving compatibility were flexible working hours (72%), opportunities to work in home office (71%), better opportunities for specialist training (51%) and enabling managerial activities on a part-time basis (73%). Both female and male physicians would like fathers to be encouraged to take parental leave to the same extent as mothers (50%). They would, e.g., like to see more flexible drop-off and pickup times for children (71%) and more childcare options offered by their employer (61%)., Conclusion: Results suggest various options for promoting compatibility of family life and work, e.g., by family-friendly working time models and part-time offers breaking with traditional role models. Managerial positions might be offered on a regular part-time basis. Structured qualification programs could enable the compatibility of clinical work, research and family life. Childcare services should preferably be provided in line with existing needs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: VIG: Consulting or advisory board membership: Jazz Pharmaceuticals; Speakers bureau: Abbvie, Janssen, Pfizer; Travel or accommodation expenses: AbbVie. PP: Consulting or advisory board membership: AbbVie, Agios, Astellas, Astex, Bristol-Meyers Squibb, Celgene, Jazz, Novartis, Otsuka, Pfizer, Sunesis; Speakers bureau: AbbVie, Agios, Astellas, Bristol-Meyers Squibb, Celgene, Jazz, Novartis, Pfizer; Travel or accommodation expenses: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Janssen, Novartis, Takeda. RFS: Consulting or advisory board membership: Abbvie, Agios, Astellas, Celgene, Daiichi Sankyo, Hexal, Neovio Biotech, Novartis, Pfizer, Roche; research funding: Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, Roche; speakers bureau, Astellas, Pfizer. SF: Consulting or advisory board membership: Bayer, Illumina, Roche; honoraria: Amgen, Eli Lilly, PharmaMar, Roche; research funding: AstraZeneca, Pfizer, PharmaMar, Roche; travel or accommodation expenses: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. AK: Consulting, honoraria, advisory board membership: Roche; research funding: BMS, Roche. RW: Consulting or advisory board: Janssen, Novartis, BMS/Celgene, Amgen, Gilead, Pfizer, Sanofi, Takeda; research funding: Janssen, Sanofi; Honoraria: Abbvie, Sanofi, Takeda, Janssen, Amgen, BMS/Celgene, Gilead, Pfizer. JW: Consulting or advisory board membership: Novartis, Bristol Myers Squibb, Celgene, Amgen, Abbvie, Agios, Jazz, Pfizer, Sanofi, Sobi, Astellas. MdW: Research funding: Pfizer, Abbvie, Novartis, Astellas, Bristol Myers Squibb, AstraZeneca, MorphoSys; speakers honoraria: AstraZeneca, Janssen; travel or accommodation expenses: Astellas, Janssen. WF: Consulting or advisory board membership: AbbVie, Amgen, Celgene, Jazz Pharmaceuticals, MorphoSys AG, Novartis, Pfizer; Stemline and Clinigen; research funding: from Amgen and Pfizer; patents and royalties: Amgen; travel or accommodation expenses: Amgen, Daiichi Sankyo, Gilead, Jazz Pharmaceuticals, and Servier. MH: Consulting or advisory board: Abbvie, BMS/Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, Tolremo. Honoraria: Jazz Pharmaceuticals, Janssen, Novartis; research funding: Astellas, Bayer Pharma AG, BergenBio, Daiichi Sankyo, Jazz Pharmaceuticals, Karyopharm, Novartis, Pfizer, Roche. FT: Consulting or advisory board: Abbvie, Astellas, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, Novartis, Pfizer. KD: Consulting or advisory board: Novartis, Celgene/BMS, Abbvie, Jazz Pharmaceuticals; research funding: Novartis; Celgene/BMS, Astellas, Agios, Kronos; Honoraria: Novartis, Celgene/BMS, Jazz Pharmaceuticals. HD: Consulting or advisory board: AbbVie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, BMS, Celgene, Daiichi Sankyo, Gilead, Janssen, Jazz, Novartis, Servier, Syndax; Clinical Research Funding to Institution: AbbVie, Agios, Amgen, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Kronos Bio, Novartis, Pfizer. All the other authors have no conflicts of interest to disclose.

Introduction: Understanding prognosis, especially long-term outcome, in advanced nonsmall cell lung cancer (NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care., Methods: Prognostic factors influencing overall survival (OS) and progression-free survival (PFS) in 2082 patients with wild-type (WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP registry recruiting in >150 centres. Analysis for pre-therapeutic factors was based on results from Cox proportional hazard models., Results: Current M-descriptors of the Union for International Cancer Control-8 staging system were validated: M1a and M1b patients had significantly longer median time to events compared to M1c (OS/PFS 16.4/7.2 months, 17.8/6.7 months and 10.9/5.4 months, respectively). OS and PFS were influenced by number and location of metastatic organ systems. M1c and four or more metastatic organs involved had shorter OS and PFS than M1c with one to three organs (OS hazard ratio (HR) 1.69, p<0.001; PFS HR 1.81, p<0.001). M1b-liver metastases had shorter OS/PFS than M1b involving other organs (OS HR 2.70, p=0.006; PFS HR 2.48, p=0.007). Based on number of involved organs (orgsys) and liver metastases, two risk groups (low-risk: M1a, M1b-non-liver, M1c-1-3-orgsys-non-liver; high-risk: M1c-liver, M1b-liver, M1c-4+-orgsys) with significantly different prognoses could be amalgamated (median OS/PFS 14.3/6.5 months and 7.7/4.1 months, respectively). Other favourable factors were female gender and Eastern Cooperative Oncology Group stage 0, with age showing no impact. Those with T1- or N0-status were associated with longer OS than T2-4 or N2-3., Conclusion: In this large observational dataset, we further defined factors for outcome in WT-NSCLC, including increased number of involved metastatic organ systems and liver metastases, as those with overall poorer prognosis and reduced survival chance., Competing Interests: M. Metzenmacher has received honoraria for advisory boards from AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche, Sanofi Aventis and Takeda. F. Griesinger has received research funding (paid to institution) from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda and Siemens, honoraria for educational lectures from AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Sanofi Genzyme, Siemens, Tesaro/GSK and Amgen, honoraria for advisory boards from Abbvie, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Genzyme, Takeda and Aria, travel support from Roche, MSD, Merck, Takeda, Boehringer Ingelheim, Abbvie, Sanofi Genzyme, BMS and AstraZeneca, and has leadership roles at Ethikkommission, Forschungskommission, Fakultätsrat University of Internal Medicine of Oldenburg. H-D. Hummel has received travel, accommodation, or other expenses from Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb and Amgen. C. Elender declares that there is no conflict of interest. H. Schäfer has received honoraria for advisory boards from Boehringer Ingelheim, BMS, Pfizer and Roche. M. de Wit reports grants from AstraZeneca, Abbvie and Novartis (paid to institution), has received honoraria for lectures and writing from AstraZeneca, support for meetings and travel from AstraZeneca and Abbvie, and has a leadership position as member of the steering committee in the German Society for Hematology and Oncology (“Deutsche Gesellschaft für Hämatologie und Onkologie”; DGHO). U. Kaiser declares that there is no conflict of interest. J. Kern has received honoraria for scientific meetings from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, travel support from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Pfizer and Roche. M. Jänicke declares that there is no conflict of interest. L. Spring declares that there is no conflict of interest. S. Zacharias declares that there is no conflict of interest. A. Kaiser-Osterhues declares that there is no conflict of interest. A. Groth has received research funding (paid to the employer AIO-Studien-gGmbH) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Roche and Takeda. A. Hipper has received research funding (paid to the employer AIO-Studien-gGmbH) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Roche and Takeda. G. Zaun declares that there is no conflict of interest. S. Dörfel declares that there is no conflict of interest. B. Güldenzoph has received advisory board honoraria from MSD Oncology, Roche Pharma AG, Amgen and AstraZeneca, and support for travel from Amgen. L. Müller declares that there is no conflict of interest. J. Uhlig has received honoraria for advisory boards and workshops from: Roche, Amgen, Servier, MSD, Bristol-Myers Squibb, Sanofi, Merck, Celgene, Novartis, Janssen-Cilag, Boehringer Ingelheim, Bayer and Biogene. M. Thomas has received honoraria for scientific meetings from AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, advisory board honoraria from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, travel support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai, Janssen Oncology, Lilly, MSD, Novartis, Pfizer, Roche and Takeda, research funding (paid to institution) from AstraZeneca, Bristol-Myers Squibb, Roche and Takeda. M. Sebastian has received research funding (paid to institution) from AstraZeneca, honoraria for advisory boards from AstraZeneca, BMS, MSD/Merck, Roche, Pfizer, Novartis, Boehringer Ingelheim, Takeda, Abbvie, Johnson & Johnson, Amgen, Tesaro and Eli Lilly, honoraria for educational lectures from AstraZeneca, BMS, Novartis, Pfizer, Boehringer Ingelheim, Roche, Lilly, Pfizer, Takeda, Sanofi, GSK, Amgen, MSD, Janssen-Cilag and Eli Lilly, travel support from BMS and Pfizer, patents from CureVax, BioTech, AstraZeneca, Boehringer Ingelheim, Novartis, BMS, Roche, Lilly, Pfizer, Takeda, Sanofi, GSK, Amgen, MSD and Janssen-Cilag. W.E.E. Eberhardt has received honoraria from AstraZeneca, Roche Pharma AG, Bristol Myers Squibb, MSD Oncology, Boehringer Ingelheim, Lilly, Takeda, Pfizer, Amgen, Novartis, Roche, Sanofi Aventis and Abbvie, consulting or advisory role for AstraZeneca, Roche, Bristol Myers Squibb, MSD Oncology, Bayer Health, Lilly, Boehringer Ingelheim, Takeda, Pfizer, MSD/Merck, Novartis, Takeda, Sanofi Aventis, Abbvie, Amgen, Bayer and Janssen-Cilag, research funding from AstraZeneca, Lilly and Bristol Myers Squibb, and is a member of the IASLC Staging Committee, M-track., (Copyright ©The authors 2023.)

The incidence of aggressive B-cell lymphomas increases with age, but for elderly or frail patients not eligible for doxorubicin-containing treatment standard therapy remains to be defined. In this prospective, multicenter, phase-2 B-R-ENDA trial, we investigated the feasibility, toxicity, and efficacy of 8 cycles rituximab combined with 6 cycles bendamustine (BR) in elderly or frail aggressive B-cell lymphoma patients: 39 patients aged >80 years and 29 patients aged 61-80 years with elevated Cumulative Illness Rating Scalescore >6 were included. Progression-free survival (PFS) and overall survival (OS) at 2 years were 45% (95% confidence interval [CI], 28%-61%) and 46% (28%-63%) for the patients age >80, as well 32% (13%-51%) and 37% (17%-57%) for frail patients age 64-80, respectively. In a preplanned retrospective analysis, we found no significant differences in PFS and OS comparing the outcome of the 39 patients age >80 years with 40 patients aged 76-80 years treated with 6xR-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and 2 x rituximab in the RICOVER-60 trial (DSHNHL 1999-1, NCT00052936, EU-20243), yet we detected lower rates of infections and treatment-related deaths in the BR-treated patients. We demonstrate that older and frail patients with aggressive B-cell lymphoma who are not able to receive standard CHOP-based therapy can benefit from anthracycline-free therapy as a feasible and effective therapeutic option., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Objective: By implementing a focused must-have vaccination strategy (Easy Vaccination in Oncology [EVO]), we aimed to increase rates for high-impact vaccinations (Streptococcus pneumoniae, influenza, herpes zoster and hepatitis B) in the at-risk population of oncological patients., Methods: In this German multicentre interventional non-randomised controlled two-arm open trial with repeated cross-sectional data collection, we evaluated the EVO strategy as an easy to implement approach. Vaccination rates were assessed in the outpatient setting and re-assessed after 3 months. A generalised linear mixed model (GLMM) was used to assess the primary endpoint (Streptococcus pneumoniae vaccination rates according to recommendations), taking clustering within clinics into account., Results: Vaccination rates substantially increased in the intervention group; Streptococcus pneumoniae +21.5% (+16.7% according to recommendations), influenza +12.2%, herpes zoster +13.3% (+13.6% age group 50+), and hepatitis B +11%. Vaccination rates in the control group tended to decrease or increase only moderately (-5.8% [-3.8%], +7.4%, +2.1% [1.4%], and -1.7%, respectively). GLMM showed significant effect of the intervention (OR 7.50, 95% CI 2.18-25.80, p = 0.001)., Conclusion: This easy-to-implement and resource-saving approach has the potential to increase vaccination rates in oncological patients and to have a considerable impact protecting oncological patients from preventable infectious diseases., Clinical Trial Registration: The study was registered at the German Resister for Clinical Studies (DRKS) under DRKS00020118., (© 2022 John Wiley & Sons Ltd.)

Aim: Monitoring electronic patient-reported outcomes (ePRO) can provide various benefits to cancer patients, such as enhanced quality of life, reduction of hospital admissions, and even prolonged survival. Furthermore, ePRO might offer significant benefits to patients under antineoplastic treatment in the context of the current COVID-19 pandemic. However, evidence on feasibility of ePRO in routine cancer care and barriers met in a real-life setting remains limited., Subject and Methods: We conducted a feasibility study among patients diagnosed with multiple myeloma currently under antineoplastic treatment. Patients filled out weekly ePRO questionnaires and were followed up for 6 months. In case of adverse events, an alert was sent to the clinic. We assessed uptake and adherence, as well as subjective perceptions of patients and clinic staff. A semi-structured literature review was conducted to contextualize results., Results: Eleven patients were recruited and followed up for 6 months. Overall adherence was found at a high level and remained stable throughout the study period. Feedback from patients was positive; however, clinic staff expressed disappointment and frustration, criticising an increase of workload while not perceiving any benefit to the oncological treatment. Both findings were backed by evidence we found in literature., Conclusions: Implementation of ePRO monitoring to routine cancer treatment seems to be feasible regarding patients' acceptance and compliance. However, integration of the tool into clinical workflow without increasing workload and deterring clinicians proves to be a major challenge., Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-022-01767-3., Competing Interests: Competing interestsThe authors declare that they have no disclosures or competing interests (financial or non-financial) related to this study.Conflict of interestThe ePROM evaluated was provided by Noona® in the context of a test trial in the clinic. There was contract or agreement in regard to the study., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Analysis of circulating free DNA (cfDNA) is a promising tool for personalized management of colorectal cancer (CRC) patients. Untargeted cfDNA analysis using whole-genome sequencing (WGS) does not need a priori knowledge of the patient´s mutation profile., Methods: Here we established LIquid biopsy Fragmentation, Epigenetic signature and Copy Number Alteration analysis (LIFE-CNA) using WGS with ~ 6× coverage for detection of circulating tumor DNA (ctDNA) in CRC patients as a marker for CRC detection and monitoring., Results: We describe the analytical validity and a clinical proof-of-concept of LIFE-CNA using a total of 259 plasma samples collected from 50 patients with stage I-IV CRC and 61 healthy controls. To reliably distinguish CRC patients from healthy controls, we determined cutoffs for the detection of ctDNA based on global and regional cfDNA fragmentation patterns, transcriptionally active chromatin sites, and somatic copy number alterations. We further combined global and regional fragmentation pattern into a machine learning (ML) classifier to accurately predict ctDNA for cancer detection. By following individual patients throughout their course of disease, we show that LIFE-CNA enables the reliable prediction of response or resistance to treatment up to 3.5 months before commonly used CEA., Conclusion: In summary, we developed and validated a sensitive and cost-effective method for untargeted ctDNA detection at diagnosis as well as for treatment monitoring of all CRC patients based on genetic as well as non-genetic tumor-specific cfDNA features. Thus, once sensitivity and specificity have been externally validated, LIFE-CNA has the potential to be implemented into clinical practice. To the best of our knowledge, this is the first study to consider multiple genetic and non-genetic cfDNA features in combination with ML classifiers and to evaluate their potential in both cancer detection and treatment monitoring. Trial registration DRKS00012890., (© 2022. The Author(s).)

Treatment of metastasized malignant melanoma still has very limited therapeutic options. After exhaustion of immuno-checkpoint inhibition (ICI) and potentially targeted therapy, no promising alternatives are currently available. We report on an 83-year-old patient suffering from disseminated metastatic melanoma who showed an almost complete response to ICI following chemotherapy, after repeated failure of different regimens including two nonresponsive regimens of ICI. The presented outcome suggests a cytotoxic immuno-priming, facilitating a response to prior nonresponsive ICI. As this concept has not been established until now for malignant melanoma, in contrast to multiple other cancer entities, our case report corroborates previous evidence and therefore suggests a new treatment option, which should be researched further., Competing Interests: The authors declare no conflict of interest to declare., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: Vaccinations have the potential to significantly lower the burden of disease for many major infections in the high-risk population of hematological and oncological patients. In this regard Shingrix ® , an inactivated Varicella Zoster Virus vaccine, received market approval in the European Union in March 2018, after prior US approval in October 2017, and recommendations specifically state immunocompromised, including oncological, patients. As vaccination rates are considered to be poor in oncological patients, determining the current vaccination rates for Shingrix ® two years after market approval is important in defining the need for intervention to bring this potentially high-impact vaccine to the patients., Methods: We analyzed data of the EVO Study to provide data for Herpes zoster vaccination rates in oncological patients. The EVO Study was an interventional study evaluating the potential of increasing vaccination rates of specified must-have vaccinations by an instructional card in the oncological setting. Numbers presented in this publication merged baseline data and follow-up data of the control group; hence data not affected by the intervention., Results: Data of 370 patients were analyzed; 21.1% with hematological malignancies and 78.9% with solid cancer. Only 3.0% were vaccinated with Shingrix ® . Patients with hematological malignancy were more likely to be vaccinated than those with solid cancer (7.7 vs. 1.7%)., Conclusion: Despite clear recommendations and a pressing need in the high-risk population of hematological and oncological patients, the vast majority of patients are still left without vaccine protection against Herpes zoster by Shingrix ® .

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

Background: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population., Methods: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244., Findings: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment., Interpretation: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MPE reports receiving funding to conduct the trial from AIO Studien, the regulatory sponsor of the trial, and serving as an advisor with Bristol Myers Squibb. NMB reports receiving research funding and receipt of equipment from Deutsche Forschungsgemeinschaft. RH reports serving as an advisor with Amgen, Astra Zeneca, Bristol Myers Squibb, Boehringer, Daichi, Lilly, Merck, MSD, Pierre Fabre, Roche, and Servier; honoraria for lectures and presentations from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier; and consulting fees from Amgen, Astra Zeneca, Bayer, BMS, Boehringer, Daichi, Lilly, medac, Merck, MSD, Pierre Fabre, Roche, Saladax, Sanofi, and Servier. AV reports serving as an advisor with Roche, Bayer, Bristol Myers Squibb, Lilly, Eisai, AstraZeneca, IPSEN, MSD, Sirtex, BTG, Servier, Terumo, and Imaging Equipment; and consulting fees and honoraria for lectures from Roche, Bayer, Bristol Myers Squibb, Lilly, Eisai, Astra Zeneca, IPSEN, MSD, Sirtex, BTG, Servier, Terumo, and Imaging Equipment. RJ reports receiving consulting fees from Roche and Bayer; payments for lectures and presentations from Dr Falk Pharma and Bristol Myers Squibb; for writing of manuscripts from Boston Scientific and Springer Nature; serving as an advisor with Heidelberg University Hospital; and leading the Endoscopy section of the German Society of Gastroenterology. PTP reports receiving consulting fees from Bristol Myers Squibb, AstraZeneca, and MSD. TGa reports receiving honoraria from Bristol Myers Squibb, MSD, and Roche for presentations and advisory functions. JNK reports receiving consulting fees from Owkin and Panakeia as well as honoraria for lectures from MSD and Eisai. MM reports employment with AIO Studien, who was the regulatory sponsor of the trial. NH reports serving as an advisor with Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Cancer-associated venous thrombosis (CAT) is a common and serious complication of active malignancies, increasing in frequency during systemic treatment and radiotherapy. Due to a high risk of recurrence and bleeding, the administration of anticoagulants for initial treatment and secondary prevention of CAT is challenging. We conducted a prospective registry study of patients with acute CAT to evaluate the way treatment is given to these patients in routine practice., Methods: From May 2015 to May 2017, all consecutive patients with acute venous thromboembolism (VTE) admitted to specialty or emergency departments of the participating hospitals in Berlin, Germany, were entered into the registry. Patients with cancer underwent extensive baseline evaluation including the type and location of thrombosis and use of anticoagulant therapy. Follow-up assessments were made at discharge and by telephone interviews at 3 and 6 months., Results: A total of 382 patients with acute CAT were enrolled in the study, representing 24.5% of all patients with thrombosis. 70.4% of CAT patients had deep vein thromboses (DVT), 48.2% had pulmonary embolism (PE), and 18.6% had concurrent PE and DVT. A significant proportion of VTE (27%) was asymptomatic and was diagnosed only incidentally. At baseline, 97.9% of the patients received anticoagulant therapy, predominantly with low-molecular-weight heparin (LMWH) (n = 334, 87.4%). Direct oral anticoagulants (DOACs) were given to 5.8% of patients, and vitamin K antagonists were rarely used (<2% of patients). Changes in the prescription of antithrombotic agents were seen at discharge from hospital and during follow-up. Overall, the use of LMWH declined during follow-up, while the proportion of patients treated with DOACs increased to 32.4% at 6 months. At baseline, the most frequently used LMWH were enoxaparin and nadroparin, but many patients were switched to once daily tinzaparin prior to discharge. Initially and after discharge, the majority of patients were treated by oncologists. Overall, 263 (68.8%) and 222 (58.1%) patients were still alive and could be contacted at 3 and 6 months of follow-up, respectively. Of these, 84.0% and 71.6% were still on anticoagulant therapy (58.6% and 36.5% on LMWH)., Conclusion: In accordance with the guidelines, the majority of CAT patients received anticoagulation therapy for the recommended minimum duration of 3-6 months. LMWH remained the preferred option throughout the study, demonstrating good patient adherence. In deviation from guideline recommendations and available study results during the study period, more than a quarter of CAT patients were treated with DOACs. Only recently, DOACs have been established as another option for anticoagulation in CAT patients., (© 2021 S. Karger AG, Basel.)

Standard operating procedures for autologous stem cell transplantation (SCT) aim to guarantee best possible engraftment. Three procedures are routinely used for transplant infusion: regular bag infusion (Procedure 1), injection via syringe (Procedure 2), and combination of regular bag infusion and syringe (Procedure 3). We conducted a retrospective analysis of all autologous stem cell transplants done in the hematology department of the Vivantes Clinic Neukoelln in Berlin, Germany, between January 1, 2016 and March 4, 2017. Of the total of 69 patients, 17 underwent Procedure 1, 32 Procedure 2, and 20 Procedure 3. Although speed of transplant reinfusion differed significantly between procedure types, these differences had no effect on duration of leukopenia. However, duration of leukopenia did correlate with need for blood transfusion and use of antibiotics. Our findings contradict the general perception that very rapid reinfusion is necessary. Nevertheless, considering the limitations of this study (retrospective, single center, small sample size) and that longer duration of aplasia is associated with greater need for intervention, efficient transplant reinfusion is advisable. More research is needed regarding timeliness and type of procedure used., (© 2021. Japanese Society of Hematology.)

Objective: Patients suffering from haemato-oncological diseases tend to have a weakened immune system after the end of their therapy. To avoid infections, patients are advised to limit contact with other people. This poses the question whether a stay at a rehabilitation facility can be recommended., Methods: We report about 134 rehabilitation stays of patients. Premature discontinuation of the rehabilitation stay was selected as the criterion for a serious complication during the rehabilitation, and the underlying reasons were analysed., Results: Compared to the discontinuation rates of patients suffering from solid tumours (2.4%), the percentage of haemato-oncological patients ending prematurely their rehabilitation stay (8.2%) is significantly increased. This rises to 17.1% for patients who have undergone an allogeneic stem cell transplantation. The analysis of the discontinuation reasons revealed that they were not directly connected to the rehabilitation. Apart from the already known risk factors for premature termination of the rehabilitation stay, we have identified the period (days) between the last therapy and the beginning of the rehabilitation stay as a risk factor., Conclusions: We show for the first time that a rehabilitation stay does not pose additional risks for patients suffering from haemato-oncological diseases., (© 2019 John Wiley & Sons Ltd.)

Purpose: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML)., Patients and Methods: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m 2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety., Results: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms., Conclusion: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

Background: In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs)., Methods: PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1-42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and EudraCT, 2014-000336-42., Findings: Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1-29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 [95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [-1·91 to 3·30] in the placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [-0·51 to 3·34]), chest pain (-3·1 [-4·57 to -1·60] vs -3·5 [-5·68 to -1·29]), fatigue (-3·0 [-4·53 to -1·50] vs -5·2 [-7·45 to -2·98]), appetite loss (-5·8 [-7·28 to -4·36] vs -7·0 [-9·17 to -4·87]), physical functioning (0·1 [-1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [-0·25 to 3·81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI -1·89 to 4·11), dyspnoea (1·6, -0·58 to 3·87), chest pain (0·4, -2·13 to 2·93), fatigue (2·2, -0·38 to 4·78), appetite loss (1·2, -1·27 to 3·67), physical functioning (-1·9, -3·91 to 0·15), or global health status or quality of life (0·8, -1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints., Interpretation: Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs., Funding: AstraZeneca., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874 ., (Copyright© 2019 Ferrata Storti Foundation.)

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = "dose-dense") and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = "standard"). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CR i ) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

Background:  In 2016, the first German guideline for bladder cancer was introduced. This survey evaluates current management of bladder cancer in Germany, focusing on systemic therapies and compares this to the guidelines., Material and Methods:  More than 4000 urologists and oncologists in Germany received a questionnaire assessing surgical and systemic therapeutic management of bladder cancer. We received 278 evaluable responses., Results:  This is the largest nationwide survey evaluating current bladder cancer management in Germany. Management can be optimised of non-muscle invasive bladder cancer including intravesical instillation therapies, as well as of muscle invasive bladder cancer including (neo)adjuvant chemotherapies, particularly with respect to the numbers of chemotherapy courses. Management of metastasised bladder cancer is predominantly performed according to the guidelines., Conclusions:  Adherence to bladder cancer guidelines in Germany can be optimised and could possibly decrease cancer-specific mortality, supported by the development of novel diagnostic and therapeutic options., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To determine predictive/prognostic factors for patients with metastatic breast cancer (MBC) receiving first-line monochemotherapy using biomarker analysis and geriatric assessment (GA)., Materials and Methods: Karnofsky Performance Status (KPS) and GA as clinical parameters, and prognostic inflammatory and nutritional index (PINI), and Glasgow prognostic score (GPS) as biomarkers were analyzed for association with clinical outcome within the randomized phase III PEg-LIposomal Doxorubicin vs. CApecitabin iN MBC (PELICAN) trial of first-line pegylated liposomal doxorubicin (PLD) or capecitabine., Results: Of 210 patients, 38% were >65years old. GA (n=152) classified 74% as fit, 10% as compromised, and 16% as frail. Biomarkers showed no age dependency. In multivariate analysis (n=70) KPS, GA, cumulative illness rating scale-geriatrics (CIRS-G), and GPS were significantly associated with time to progression, and KPS, CIRS-G, and instrumental activities of daily living (IADL) from GA, and PINI showed a significant correlation with overall survival., Conclusion: GA evaluation was feasible. KPS significantly correlated with efficacy outcomes. Items of a GA and biomarkers of inflammation and nutrition may have prognostic significance in patients with MBC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy., Methods: We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety., Results: Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events., Conclusions: Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC)., Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m 2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m 2 every 28 days or capecitabine 1250 mg/m 2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP)., Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838-1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31)., Conclusion: Both PLD and capecitabine are effective first-line agents for MBC., Competing Interests: Compliance with ethical standardsConflict of interestMShmidt is named inventor on patent applications regarding prediction of chemotherapeutic response in breast cancer and molecular markers for breast cancer prognosis. Consultant for Pfizer, Roche, Eisai, Celgene, Novartis, TEVA, and Sividon. He has received honoraria from AstraZeneca, Novartis, Pfizer, Celgene, Pierre-Fabre, GlaxoSmithKline, Eisai, Roche, Sividon, TEVA, and Amgen. He has also received previous funding from Bayer Healthcare AG, Sanofi-Aventis, and Bundesministerium für Bildung und Forschung (BMBF). DW was an employee of Shering-Plough Corp. and MDS Sharp & Dohme at the time the study was conducted. NH, SS, EJ, LM, RK, BO, JD, MW, MScholz, MU, MdW, JB, HJL, PHarnet, DA, PHarter, MB and SEAB declare no conflicts of interest.

We studied the influence of comorbidities on remission rate and overall survival (OS) in patients with chronic myeloid leukemia (CML). Participants of the CML Study IV, a randomized 5-arm trial designed to optimize imatinib therapy, were analyzed for comorbidities at diagnosis using the Charlson Comorbidity Index (CCI); 511 indexed comorbidities were reported in 1519 CML patients. Age was an additional risk factor in 863 patients. Resulting CCI scores were as follows: CCI 2, n = 589; CCI 3 or 4, n = 599; CCI 5 or 6, n = 229; and CCI ≥ 7, n = 102. No differences in cumulative incidences of accelerated phase, blast crisis, or remission rates were observed between patients in the different CCI groups. Higher CCI was significantly associated with lower OS probabilities. The 8-year OS probabilities were 93.6%, 89.4%, 77.6%, and 46.4% for patients with CCI 2, 3 to 4, 5 to 6, and ≥7, respectively. In multivariate analysis, CCI was the most powerful predictor of OS, which was still valid after removal of its age-related components. Comorbidities have no impact on treatment success but do have a negative effect on OS, indicating that survival of patients with CML is determined more by comorbidities than by CML itself. OS may therefore be inappropriate as an outcome measure for specific CML treatments. The trial was registered at www.clinicaltrials.gov as #NCT00055874., (© 2015 by The American Society of Hematology.)

Complete or partial loss of dihydropyrimidine dehydrogenase (DPD or DYPD) function has been described in cancer patients experiencing severe side effects upon administration of the fluoropyrimidine anticancer drug 5-fluorouracil (5-FU). To investigate a genetic predisposition for 5-FU intolerance due to inherited DPD defects, we established a mutation detection assay based on denaturing HPLC. Analyzing four individuals with symptoms of 5-FU-related toxicity, we detected six distinct sequence variants in the dihydropyrimidine dehydrogenase gene (DPYD): one novel mutation, c.775A>G (K259E); four known missense mutations, c.85T>C (C29R), c.496A>G (M166V), c.1601G>A (S534N), c.1627A>G (I543V); and one silent mutation c.1896T>C affecting the codon for F632. One cancer patient possessing a total of four gene mutations resulting in four amino acid substitutions (C29R, M166V, S534N, I543V) displayed significantly reduced DPD activity. The rare combination of the highly conserved mutation sites M166V and S534N was additionally found in one of the other patients. DPD enzyme activity was low, but yet within normal range. The K259E mutation did not provoke a decrease in DPD function in a heterozygous individual. Based on the protein structure of crystalline pig DPD and the deduced homology models, we have additionally investigated the amino acid positions in their three-dimensional network which correspond to the five missense mutations discovered in the patients., (Copyright 2003 Wiley-Liss, Inc.)