Search

Purpose: Recent advancements in imaging, particularly 18F-fluorodeoxyglucose positron-emission tomography-computed tomography (FDG-PET/CT), have improved the detection of involved lymph nodes, thus influencing staging accuracy and potentially treatment outcomes. This study is a post hoc analysis of the GAZAI trial data to evaluate the impact of FDG-PET/CT versus computed tomography (CT) alone on radiation target volumes for involved-site radiotherapy (IS-RT) in early-stage follicular lymphoma (FL)., Methods: All patients in the GAZAI trial underwent pretherapeutic FDG-PET/CT examinations, which were subject to central quality control. Lymph nodes with pathological metabolism were assessed for CT morphology. Differential regional involvement and the impact on radiation target volume for IS-RT were compared between PET/CT-based to solely CT-based staging., Results: In 54 patients with PET-positive lymph nodes after initial surgery, 170 involved lymph nodes were identified in total. FDG-PET/CT identified additionally involved lymph nodes not detected by CT in 61% of the patients, leading to a significant change in radiation treatment fields for 30% of the cohort. Only 58% of all involved lymph nodes exhibited pathological CT morphology. The findings were robust across different Deauville score thresholds and CT morphological metrics., Conclusion: The findings confirm the essential role of FDG-PET/CT in accurately defining the radiation volume for treatment of early-stage follicular lymphomas with radiotherapy. These results support the integration of FDG-PET/CT into the standard diagnostic pathway and its inclusion in the service catalogue of statutory health insurance, emphasizing its importance for optimal treatment planning and the potential impact on patient outcomes., Competing Interests: Conflict of interest: A. Wark, J.-Y. Kim, E. Mavriopoulou, C. la Fougère, T. Wiegel, C.W. Scholz, C. Baues, M. Li, T. Gauler, S.E. Combs, and K. Herfarth declare that they have no competing interests., (© 2025. The Author(s).)

Purpose: To characterize real-world attrition rates across first-line (1L) to third-line (3L) therapies in patients with HER2-positive (HER2 +) metastatic breast cancer (mBC) receiving routine care in seven hospital systems across Europe (France, Germany, Italy, Spain, and the UK)., Methods: This retrospective, observational, multi-country, cohort study collected electronic medical record data from women aged ≥ 18 years diagnosed with HER2 + mBC from 2017-2021. The primary endpoint was attrition rate (the proportion of patients receiving a line of therapy [LOT] with no further evidence of subsequent LOTs). Key additional endpoints included treatment patterns, real-world time to treatment discontinuation (TTD), and time to next treatment (TTNT)., Results: 29.6% (95% confidence interval [CI] 25.0-34.6) and 34.2% (95% CI 27.5-41.5) of treated patients with HER2 + mBC had no further evidence of treatment beyond 1L and second-line (2L) therapy, respectively. Attrition was primarily owing to death, move to end-of-life palliative care, loss to follow up, and "other" reasons. Treatment patterns were generally aligned with clinical guidelines. Decreases in TTD (12.1 months [95% CI 10.4-14.5] for 1L, 8.9 months [95% CI 7.3-11.9] for 2L, 6.4 months [95% CI 5.2-8.9] for 3L) and TTNT (15.4 months [95% CI 13.6-20.6] for 1L, 13.5 months [95% CI 10.8-19.4] for 2L) were observed with each subsequent LOT., Conclusion: Results unveil a large proportion of patients who do not benefit from state-of-the-art subsequent LOT, and suggest diminishing effectiveness with each subsequent LOT., Competing Interests: Declarations. Conflict of interest: The authors declare the following competing interests: N.H. has received lecture honoraria from Art Tempi, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Medscape, MSD, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi, Seagen, Viatris, and Zuelligpharma; has received consulting or advisory honoraria from Aptitude Health, Gilead, Pfizer, Sandox-Hexal, Sanofi, and Seagen; has received research funding from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Gilead, MSD, Roche, Seagen, TRIO, and WSG; has participated on IDMC/steering committees for Lilly, Pierre Fabre, and Roche; and has ownership interest in the West German Study Group. E.C. has received lecture, consulting, or advisory honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Menarini, MSD, Novartis, Pfizer, Reveal Genomics, and Roche; has received support for attending meetings and/or travel from AstraZeneca, Pfizer, and Roche; has received research funding from Daiichi Sankyo, Pfizer, and Roche; and has participated on steering committees for AstraZeneca, Daiichi Sankyo, Gilead, Novartis, Reveal Genomics, and Roche. G.J. has received consulting honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Diaccurate, Lilly, Novartis, Pfizer, Roche, and Seagen; has received honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche, and Seagen; has received support for attending meetings and/or travel from Amgen, AstraZeneca Bristol Myers Squibb, Gilead, Lilly, Novartis, Pfizer, and Roche; and has received medical writing support from Amgen, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, and Roche. V.M. has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Gilead, high5 Oncology, iMED Institut, Lilly, Medac, Medscape, MSD, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche, and Seagen; has received consulting or advisory honoraria from ClinSol, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pierre Fabre, PINK, Roche, and Stemline; and has received research funding from AstraZeneca, Genentech, Novartis, Roche, and Seagen. N.N. has received consulting or advisory honoraria from AstraZeneca, Chugai Pharmaceutical, and Daiichi Sankyo; has received lecture honoraria from AstraZeneca, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku, and Pfizer Japan; and has received research funding from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku, and Pfizer Japan. G.V. has received research grants from Dako/Agilent Technologies, Roche/Genentech, and Ventana Medical Systems, and has received honoraria from AstraZeneca, Daiichi Sankyo, Dako/Agilent, Gilead, MSD Oncology, Pfizer, Roche, and Ventana. R.B. has held advisory roles at AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Grünenthal, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, and Stemline; has received lecture honoraria from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Grünenthal, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, and Stemline; and has received research support from Daiichi Sankyo, MSD, Novartis, and Roche. C.K. has received lecture honoraria from AstraZeneca, Eli Lilly, Genomic Health, Gilead, GSK, Novartis, PharmaMar, Pfizer, and Roche; has received consulting or advisory honoraria from AstraZeneca, Eli Lilly, Genomic Health, Gilead, GSK, MSD, Novartis, PharmaMar, and Roche; and has participated on steering committees for AstraZeneca. M.J.H. has received lecture honoraria from AstraZeneca. R.M.C. has received an unrestricted educational grant from Pfizer; has received research support from AstraZeneca, Daiichi Sankyo, MSD Ireland, and Pfizer; has received honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, and Seagen; and has received support for attending meetings and/or travel from Gilead, Novartis, and Roche. M.G. has received support for attending meetings and/or travel from AstraZeneca, Gilead, Roche, and Pfizer, and has received honoraria from AstraZeneca, Gilead, and Pfizer. V.G. has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, Menarini Stemline, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre, and Roche; has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Menarini Stemline, Novartis, Roche, and Zentiva; and has received expert testimony honoraria from Eli Lilly. G.B. has received honoraria from Agendia, Amgen, AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Exact Science, Gilead, Helsinn Lilly, Menarini Stemline, MSD, Novartis, Pfizer, Roche, Sanofi, and Seagen, and has received a research grant from Gilead. H.W. has received lecture honoraria from Seagen; has received consulting or advisory honoraria from AstraZeneca, Augustine Therapeutics, Daiichi Sankyo, E Squared Communications LLC, Gilead, Immutep Ltd, Lilly, MediMix, Novartis, NV Hict, Pfizer, PSI CRO, Roche, and Stemline Therapeutics; has received support for attending meetings and/or travel from Daiichi Sankyo and Pfizer; has received research funding from Novartis, Roche, and Syneos Health; and has received subscription fees from Gilead. S.E.-d-R. has received honoraria from AstraZeneca, COR2ED, Daiichi Sankyo, Jazz Pharmaceuticals, Medistream, Pierre Fabre, Roche, and Seagen; has received research funding from AstraZeneca, Byondis, Daiichi Sankyo, Jazz Pharmaceuticals, MEDSIR, Roche, SOLTI, and Zymeworks; and has received support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Kern Pharma, Pfizer, Seagen, and SOLTI. M.P., H.B., N.K.-C., N.S., and S.V. are employees of AstraZeneca. N.K.-C. holds stocks in AstraZeneca and AbbVie. N.U.L. has received honoraria from AstraZeneca and has received research funding from AstraZeneca. The remaining authors declare no competing interests. Ethical approval: The study protocol was approved by Fondazione Policlinico Universitario Agostino Gemelli IRCCS Comitato Etico, Medizinische Ethikkommission an der Julius-Maximilians-Universität Würzburg (for University Hospital Wurzburg and Vivantes Hospital Group), HRA and Health and Care Research Wales (for Leeds Teaching Hospitals Trust and NHS Lothian, UK), CEIM Provincial de Málaga (for Unidad de Gestión Clínica Intercentros Oncology, Spain), and Comite de Revue Interne Data (for Institut Curie, France; study MR-004 compliant). Consent to participate: Not applicable. Consent to publish: Not applicable., (© 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).)

Iodine oxoacids are recognised for their significant contribution to the formation of new particles in marine and polar atmospheres. Nevertheless, to incorporate the iodine oxoacid nucleation mechanism into global simulations, it is essential to comprehend how this mechanism varies under various atmospheric conditions. In this study, we combined measurements from the CLOUD (Cosmic Leaving OUtdoor Droplets) chamber at CERN and simulations with a kinetic model to investigate the impact of temperature, ionisation, and humidity on iodine oxoacid nucleation. Our findings reveal that ion-induced particle formation rates remain largely unaffected by changes in temperature. However, neutral particle formation rates experience a significant increase when the temperature drops from +10 °C to -10 °C. Running the kinetic model with varying ionisation rates demonstrates that the particle formation rate only increases with a higher ionisation rate when the iodic acid concentration exceeds 1.5 × 10 7 cm -3 , a concentration rarely reached in pristine marine atmospheres. Consequently, our simulations suggest that, despite higher ionisation rates, the charged cluster nucleation pathway of iodic acid is unlikely to be enhanced in the upper troposphere by higher ionisation rates. Instead, the neutral nucleation channel is likely to be the dominant channel in that region. Notably, the iodine oxoacid nucleation mechanism remains unaffected by changes in relative humidity from 2% to 80%. However, under unrealistically dry conditions (below 0.008% RH at +10 °C), iodine oxides (I 2 O 4 and I 2 O 5 ) significantly enhance formation rates. Therefore, we conclude that iodine oxoacid nucleation is the dominant nucleation mechanism for iodine nucleation in the marine and polar boundary layer atmosphere., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Hodgkin lymphoma (HL) has become 1 of the most curable cancers. Therefore, rigorous assessment of health-related quality of life (HRQoL) and symptom burden of these patients is essential to support informed clinical decisions. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group previously developed the EORTC Quality of Life Questionnaire (QLQ) Hodgkin Lymphoma 27. This paper reports the final results of an international study by the EORTC group to develop a HRQoL disease-specific measure for these patients: the EORTC QLQ-HL27. Patients with a confirmed diagnosis of HL (N = 381) were enrolled from 12 countries and completed the EORTC QLQ-C30, QLQ-HL27, and a debriefing questionnaire at baseline (any time after diagnosis). A subset completed a retest (n = 126) or responsiveness-to-change analyses (RCA) second measurement (n = 98). Psychometrics were evaluated. Confirmatory factor analysis showed an acceptable fit of the 27 items of the QLQ-HL27 on its 4 scales (symptom burden, physical condition/fatigue, emotional impact, and worries about health/functioning). Test-retest reliability, convergent validity, known-group comparisons, and RCA find satisfactory results. Symptom burden and fatigue was higher among patients on treatment (with 36%-83% reporting at least a few problems) compared with those who had completed treatment (19%-61% reporting at least a few problems). Prevalence of worries about health and functioning (reporting at least some worry) was similar for patients on treatment (51%-81%) vs those who had completed treatment (52%-78%). Implementation of the EORTC QLQ-HL27 in research and clinical applications will increase sensitivity of HRQoL assessment in patients with HL. High quality data generated through use of this questionnaire are expected to facilitate clinical decision making in the HL setting., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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.)

Background: Health-related quality of life (HRQOL) is a critical aspect to consider when making treatment decisions for patients with non-Hodgkin-lymphoma (NHL). This international study by the European Organisation for Research and Treatment of Cancer (EORTC) tested the psychometric properties of two newly developed measures for patients with high-grade (HG)- and low-grade (LG)-NHL: the EORTC QLQ-NHL-HG29 and the EORTC QLQ-NHL-LG20 to supplement the core questionnaire (EORTC QLQ-C30)., Methods: Overall, 768 patients with HG-NHL (N = 423) and LG-NHL (N = 345) from 12 countries completed the QLQ-C30, QLQ-NHL-HG29/QLQ-NHL-LG20 and a debriefing questionnaire at baseline, and a subset at follow-up for either retest (N = 125/124) or responsiveness to change (RCA; N = 98/49)., Results: Confirmatory factor analysis showed an acceptable to good fit of the 29 items of the QLQ-NHL-HG29 on its five scales (symptom burden [SB], neuropathy, physical condition/fatigue [PF], emotional impact [EI], and worries about health/functioning [WH]), and of the 20 items of the QLQ-NHL-LG20 on its four scales (SB, PF, EI, and WH). Completion took on average 10 minutes. Test-retest reliability, convergent validity, known-group comparisons, and RCA find satisfactory results of both measures. A total of 31%-78% of patients with HG-NHL and 22%-73% of patients with LG-NHL reported symptoms and/or worries (e.g., tingling in hands/feet, lack of energy, and worries about recurrence). Patients reporting symptoms/worries had substantially lower HRQOL compared to those without., Discussion: The use of the EORTC QLQ-NHL-HG29 and QLQ-NHL-LG20 questionnaires in clinical research and practice will provide clinically relevant data to better inform treatment decision-making., Plain Language Summary: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group developed two questionnaires. These questionnaires measure health-related quality of life. The questionnaires are for patients with high-grade or low-grade non-Hodgkin lymphoma. They are called the EORTC QLQ-NHL-HG29 and QLQ-NHL-LG20. The questionnaires are now internationally validated. This study demonstrates that the questionnaires are reliably and valid, which are important aspects of a questionnaire. The questionnaires can now be used in clinical trials and practice. With the information gathered from the questionnaires, patients and clinicians can better evaluate treatments and discuss the best choice for a patient., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

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.)

Selecting the most appropriate chronic lymphocytic leukaemia (CLL) treatment is challenging. Patient-reported health-related quality of life (HRQoL) is therefore a critical aspect to consider. This international study by the European Organization for Research and Treatment of Cancer (EORTC) tested the psychometric properties of a newly developed measure for CLL patients: the EORTC QLQ-CLL17 to supplement the core questionnaire (EORTC QLQ-C30). Patients with CLL (n = 341) from 12 countries completed the QLQ-C30, QLQ-CLL17 and a debriefing questionnaire. Sociodemographic and clinical data were recorded from medical records. A high percentage (30%-66%) reported symptoms and/or worries (e.g. aches/pains in muscles, lack of energy and worry/fears about health). Confirmatory factor analysis showed an acceptable to good fit of the 17 items on the three scales (i.e. symptom burden, physical condition/fatigue and worries/fears about health and functioning). Completion took on average 8 min. Test-retest and convergent validity was demonstrated. The QLQ-CLL17 differentiated between patients with an Eastern Cooperative Oncology group (ECOG) performance of 0 versus 1-3 (p's < 0.01 and clinically relevant). The newly developed EORTC QLQ-CLL17 will increase sensitivity of HRQoL assessment in patients with CLL. Implementation of this questionnaire both in clinical research and practice will help to generate unique clinically relevant data to better inform CLL treatment decision-making., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Radioimmunotherapy with 90-yttrium-ibritumomab tiuxetan (90Y-IT) as first-line treatment in patients with follicular lymphoma (FL) demonstrated promising results with a complete remission (CR) rate of 56% and a median progression-free survival (PFS) of 26 months, when initially analyzed after a median follow-up of 30.6 months. The aim of this long-term follow-up was to investigate whether clinical benefits were maintained and new safety signals appeared. Fifty-nine patients, aged ≥ 50 years, with FL grade 1 to 3A in stages II to IV were treated with 90Y-IT as first-line therapy. If CR without evidence of minimal residual disease (MRD), partial response or stable disease was achieved 6 months after treatment, patients were observed without further treatment. Patients with CR but persisting MRD received consolidation therapy with rituximab. The primary endpoint was the clinical response rate. Secondary endpoints were time to progression, safety, and tolerability. After a median follow-up of 9.6 years, median PFS was 3.6 years, and 8-year PFS was 38.3%. Median overall survival (OS) was not reached during the extended follow-up, and 8-year OS amounted to 69.2%. Age 65 years and above or disease progression within 24 months of treatment were significantly associated with shorter OS. An important finding was the lack of new safety signals. In particular, no increase in secondary malignancies or transformation into aggressive lymphoma was observed compared to trials with a similar follow-up. In summary, 90Y-IT as first-line treatment demonstrates a favorable safety profile and long-term clinical activity in a substantial fraction of FL patients in need of therapy. ClinicalTrials.gov Identifier: NCT00772655., (© 2022. The Author(s).)

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.)

Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC)., Patients and Methods: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m 2 ) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient., Results: Patients received lacnotuzumab + gem-carbo ( n = 34) or gem-carbo ( n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47-8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45-7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand., Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1-CSF1 receptor pathway in TNBC., (©2021 American Association for Cancer Research.)

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P < 0.01), while there was no significant difference regarding OS or transformation. With the limitations of a retrospective analysis, these results suggest a benefit for R-CHOP over R-B in FL3A or FL1-2-3A. Confirmatory data from prospective clinical trials are needed.

To assess the efficacy of radioimmunotherapy (RIT) with 90 yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) and for relapse in 45 (50%) patients. Most patients received 90Y-IT as consolidation after chemoimmunotherapy in first line (98%) and in relapse (53%). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%. and 1 pt. (2%) PD, and for 4 pts. (9%), no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95% CI, 1.03-2.32) years, and median OS was 4.05 (95% CI, 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib.

To assess efficacy of radioimmunotherapy (RIT) in follicular lymphoma, data from 281 patients collected in the RIT Network, with a median follow-up of 8·2 years after RIT were analysed. RIT was given at first line in 18·5% and at relapse in 81·5%. Following first line therapy, 76·9% achieved complete remission (CR), 9·6% partial remission (PR), 1·9% stable disease (SD) and 1·9% had progressive disease (PD); response was not documented in 9·7%. At relapse, the rate of CR was 48·5% and that of PR was 16·6%, SD 2·6% and PD 10·5%; response was not documented in 21·8%. After median follow-up of 8·2 years, median progression-free survival (PFS) for all was 2·54 years, median overall survival (OS) was not reached. Median PFS and OS (both not reached) were significantly better in first line, compared to RIT at relapse (PFS, 2·11 years; OS, 10·8 years; P = 0·0037 and P = 0·0021, respectively). Overall 8-year PFS was 33·9%, 53·6% for first line and 29·6% for relapsed individuals. Overall 8-year OS was 58·8%, 78·1% for first line and 54·5% for relapsed patients. Thirty-five patients (12·5%) developed secondary malignancy and 16 patients (5·7%) experienced transformation into aggressive lymphoma. RIT is a safe and effective treatment option for follicular lymphoma, both at front line and relapse with an 8-year PFS of 53·6% and 29·6%, respectively., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Constitutive signaling of PI3K/Akt/mTOR plays a prominent role in malignant transformation and progression of B-cell non-Hodgkin lymphomas (B-NHL) underscoring the need for PI3K targeted therapies. The pan-class I PI3-kinase inhibitor BKM120 has shown preclinical activity in distinct malignancies and is currently tested in clinical trials. Intratumor heterogeneity is an intrinsic property of cancers that contributes to drug resistance and tumor recurrence. Here, we demonstrate that inhibition of PI3-kinases by BKM120 attenuates growth and survival of B-NHL cell lines by inducing mitotic arrest with subsequent induction of intrinsic apoptosis. BKM120-mediated downregulation of Cyclin A and activation of the CDK1/Cyclin B1 complex facilitates mitotic entry. In addition, concomitant BKM120-mediated upregulation of Cyclin B1 expression attenuates completion of mitosis, which results in mitotic catastrophe and apoptotic cell death. In Bax and Bak deficient B-NHL, which are resistant to BKM120-induced apoptosis, BKM120-induced mitotic catastrophe results in polyploidy. Upon re-expression of wt p53 in these p53 mutated cells, BKM120-induced polyploidy is strongly reduced demonstrating that the genetic status of the cells determines the outcome of a BKM120-mediated pathway inhibition. Mitotic catastrophe and unfavorable induction of polyploidy can be prevented in this setting by additional inhibition of MEK1/2 signaling. Combining MEK1/2 inhibitors with BKM120 enhances the anti-tumor effects of BKM120, prevents prognostic unfavorable polyploidy and might be a potential strategy for the treatment of B-NHL.

Purpose: The randomised, controlled OSHO#39 study showed promising results using first-line mitoxantrone, chlorambucil and prednisolone (MCP) chemotherapy plus rituximab in patients with advanced symptomatic follicular lymphoma (FL) in need of therapy. The aim of this long-term follow-up was to investigate whether clinical benefits are maintained after up to 9 years of observation., Methods: Following the 4-year follow-up of OSHO#39, 77 FL patients who received rituximab plus MCP (R-MCP) and 52 patients who received MCP (129 patients alive and not previously censored in total) were followed for 5 additional years in this prospective, non-interventional, observational study. For the efficacy analysis, data were jointly analysed with OSHO#39 data (FL intention-to-treat population: 105 patients R-MCP, 96 MCP). Patients not included in the 5-year follow-up were censored., Results: For surviving patients, median follow-up was 102 months (R-MCP) and 87 months (MCP). Although median overall survival (OS) was not yet reached, OS was longer for patients with R-MCP compared with MCP (p = 0.0057), with 8-year-survival rates of 76.1 versus 55.9%. Further time-to-event data were substantially longer for the R-MCP group than for MCP alone: median progression-free survival (PFS) was 93.4 versus 34.9 months, and median event-free survival (EFS) 89.6 versus 26.5 months. Unplanned subanalyses of patients with and without interferon maintenance showed improved PFS and EFS without an impact on OS., Conclusions: The addition of rituximab to first-line MCP chemotherapy improves clinical outcomes in advanced FL patients and translates into long-term OS benefits. R-MCP remains a promising standard option for this patient group.

Background: The efficacy of platinum- and ifosfamide-based chemotherapy regimens as salvage treatment in metastatic breast cancer (MBC) has not yet been sufficiently evaluated., Patients and Methods: Patients with MBC treated with cisplatin plus ifosfamide with (PEI) and without (PI) etoposide in our clinic between 04/2005 and 04/2014 were retrospectively analyzed., Results: A total of 20 patients (median four prior chemotherapies) treated with PEI/PI were identified, out of whom 18 were evaluable for objective response. Treatment with PEI/PI resulted in one complete remission, nine partial remissions and two cases of stable disease. The median (range) progression-free survival was 4 (0-18) months and median overall survival from therapy initiation was 8.5 (0-50) months. PEI/PI therapy caused grade 3/4 toxicities (mainly hematological) in 80% of patients., Conclusion: PEI/PI is an adequate salvage treatment for patients with MBC but cannot be generally recommended due to toxicity. However, comparison with platinum monotherapy trials suggests that PEI/PI might be a more effective treatment for patients with triple-negative breast cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Cough, diarrhea, pyrexia and rash were observed in five patients (33%) each. Grade 3/4 events included leukopenia in 6 (40%), neutropenia in 4 (27%) and thrombocytopenia in 2 patients (13%). An objective response was observed in 14/15 patients (93%), including 5 complete response (33%; all MCL). After a median follow-up of 19 months, 67% of patients are without signs of progression. Temsirolimus can be safely added to BR with promising preliminary activity. Recruitment in phase II is ongoing.

Transformation of follicular lymphoma (FL) into aggressive disease and relapse of de novo diffuse large B cell lymphoma (DLBCL) are considered highly unfavourable events. However, most published data were acquired when rituximab was not routinely used. We retrospectively analysed 50 patients with transformed FL (tFL) in a multicenter study and compared them to 50 individuals with relapsed DLBCL (rDLBCL) who all obtained rituximab for the treatment of their disease. Our goal was to identify factors that predict a more favourable prognosis. After a median follow-up of 5.4 years from diagnosis, there was no significant difference in median overall survival (OS) from the date of transformation (tFL) or date of the first relapse (rDLBCL) (1.9 versus 3.9 years, P = .542). Of note, 5-year OS of patients with tFL was 46 %. Follicular lymphoma patients, treatment naïve prior to transformation, fared significantly better than pretreated patients (median not reached versus 1.4 years, P = .014). Regarding rDLBCL, female gender (13.9 versus 1.8 years, P = .019) and absence of rituximab prior to the first relapse (14.0 versus 1.8 years, P = .035) were favourable prognostic factors in a uni- and multivariate analysis. Only a proportion of patients received high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT), i.e. 38 and 52 % of patients with tFL and rDLBCL, respectively. Our data indicate that a favourable prognosis is conferred by treatment naivety in tFL and by rituximab naivety in rDLBCL. In contrast, we did not find a prognostic impact of HDT-ASCT in our series.

Purpose: Very few reliable clinical data about the use of radioimmunotherapy in aggressive B-cell lymphoma exist., Methods: Patients with aggressive B-cell lymphoma registered in the international RIT-Network were analysed with regard to prior treatment, response and side effects. The RIT-Network is a web-based registry that collects observational data from radioimmunotherapy-treated patients with malignant lymphoma across 13 countries., Results: This analysis included 215 with aggressive B-cell lymphoma out of 232 patients registered in the RIT-Network. Histological subtypes were as follows: 190 diffuse large B-cell, 15 primary mediastinal, 9 anaplastic large cell, and 1 intravascular lymphoma. The median age of the patients was 62 years (range 17 - 88), with 27% above the age of 70 years. Radioimmunotherapy was mainly used as consolidation after first-line or second-line chemotherapy (56.1%), as part of third-line to eighth-line therapy for relapse (16.4%), and in refractory disease (12.2%). Grade IV neutropenia and thrombopenia and grade III anaemia were observed. The median time to recovery of blood count was 81 days (range 0 - 600 days). The overall response rate was 63.3%. The complete response rate was 76.4 % in patients treated as part of first-line therapy, and 44.3% in patients with relapse. Mean overall survival in first-line therapy patients was 32.7 months and 14.0 months in patients with relapse or refractory disease, respectively., Conclusion: Most patients with aggressive B-cell lymphoma in the RIT-Network received radioimmunotherapy as consolidation after first-line therapy with excellent complete remission and overall survival rates compared to published data. In relapsed aggressive B-cell lymphoma, radioimmunotherapy is a safe and feasible treatment leading to satisfactory response rates with acceptable toxicity.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive lymphoma, with a great demand for novel treatments for relapsing and refractory disease. Constitutive activation of the phosphatidyl-inositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is often detected in this lymphoma. Inhibition of this signaling cascade with the pan-class I PI3K inhibitor NVP-BKM120 decreased cell proliferation and increased apoptotic cell death. DLBCL proliferation was further decreased if NVP-BKM120-induced autophagy was blocked. Treatment with NVP-BKM120 was associated with an increase of the pro-apoptotic BH3-only proteins Puma and Bim and down-regulation of the anti-apoptotic Bcl-xL and Mcl-1. Translation of Bcl-xL and Mcl-1 is facilitated by cap-dependent mRNA translation, a process that was partially inhibited by NVP-BKM120. Overall, we demonstrated here the potential of NVP-BKM120 for the treatment of DLBCL.

Background: Marginal zone lymphoma (MZL) is a non-Hodgkin lymphoma that occurs as extra nodal, nodal, or splenic. While MZL is generally considered an indolent disease, a substantial percentage of patients follow an unfavorable course. The objective of this retrospective analysis was to identify predictors for a reduced overall survival (OS), or conversely an increased OS., Patients and Methods: One hundred and ninety-seven MZL patients were analyzed. Apart from assessing previously published risk factors, concomitant morbidity at diagnosis, transformation into aggressive lymphoma, and occurrence of additional malignancies were evaluated., Results: Next to the known risk factors, i.e. above 60 years of age and elevated serum lactate dehydrogenase (LDH), we demonstrate that transformation into aggressive lymphoma, as well as additional malignancies, are important independent risk factors for a shortened OS in a multivariate analysis, irrespective of the MZL localization. Impressively, in the group of patients lacking LDH elevation, transformation, and/or additional malignancies, only 1 of 63 patients died during follow-up compared with 37 of 87 patients in the high-risk group (HR = 22.8; 95% confidence interval 3.1-167.0; P = 0.002)., Conclusions: Our analysis proposes novel risk factors and warrants for a continuous follow-up to detect the occurrence of transformation and additional malignancies early on.

Mantle cell lymphoma (MCL) is an aggressive form of Non-Hodgkin-lymphoma (NHL) with an ongoing need for novel treatments. Apart from the translocation t(11:14), which facilitates constitutive transcription of cyclin D1, additional aberrations are frequently observed in MCL, including a recurrent dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. mTOR, a key component of this pathway, is pivotal for the assembly of mTOR complex (mTORC) 1 and 2. Temsirolimus, an analog of the mTOR inhibitor rapamycin, is approved for the treatment of relapsed MCL. Response rates, however, are low and response durations are short. We demonstrate that inhibition of mTORC1 by rapamycin or blocking of mTORC1 and mTORC2 in conjunction with PI3K by NVP-BEZ235 reduces proliferation of MCL cell lines to a similar extent. However, only NVP-BEZ235 is able to sufficiently inhibit the downstream pathway of mTOR and to mediate cell death through activation of the intrinsic apoptosis pathway. Further analysis demonstrated that the anti-apoptotic Bcl-2 family member Mcl-1 plays a central role in regulation of MCL survival. While Mcl-1 protein levels remained unchanged after coculture with rapamycin, they were down-regulated in NVP-BEZ235 treated cells. Furthermore, inhibition of Mcl-1 by the BH3-only mimetic obatoclax or down-regulation of constitutive Mcl-1, but not of Bcl-2 or Bcl-xL, by siRNA facilitated cell death of MCL cells and enhanced NVP-BEZ235's capacity to induce cell death. Our findings may help to lay the foundation for further improvements in the treatment of MCL., (Copyright © 2013 UICC.)

Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is frequently dysregulated in diffuse large B cell lymphoma (DLBCL) including the favorable germinal centre B-cell (GCB) and the unfavorable activated B-cell (ABC) subtypes. mTOR promotes cap-dependent translation of proteins, like Mcl-1, through inhibitory phosphorylation of the eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Inhibition of mTOR by RAD001 reduces proliferation but fails to dephosphorylate 4EBP1 and to induce cell death in either DLBCL subtype. In contrast, concurrent inhibition of PI3K and mTOR with NVP-BEZ235 inhibits proliferation, dephosphorylates 4EBP1, and induces cells death, notably more pronounced in CGB cells. Small RNA interference identifies Mcl-1 as a crucial cell death mediator of both DLBCL subtypes. Inhibition of the PI3K/mTOR/4EBP1 by NVP-BEZ235 results in suppression of the cap-dependent translation initiation complex and concomitant downregulation of Mcl-1 in GCB cell lines. In ABC cell lines, this suppression is possibly compensated by NF-κB- or Pim kinase-mediated signaling., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aim: Despite advances in the the first- and second-line treatment of metastatic breast cancer, there remains a large unmet need for additional treatment options. As preclinical studies have suggested that combining everolimus with carboplatin may produce higher activity than each drug by itself, we initiated a phase I study of this combination., Patients and Methods: Patients with pre-treated metastatic breast cancer received weekly carboplatin at AUC2 and daily oral everolimus at different dose-levels (level I: 2.5 mg; II: 5 mg; III: 7.5 mg; IV: 10 mg). Three patients were assigned to dose-levels I to III, and six to dose-level IV. The primary end-point was to determine the maximum tolerated dose (MTD)., Results: Fifteen patients were recruited to the study. The median number of previous chemotherapies was four (range: 1-11). No dose-limiting toxicity occurred at levels I-III during the first cycle. Based on the pre-determined definition, the maximum planned dose-level IV was selected as the MTD. Patients received a median of four cycles of treatment (range 1-13). Most frequent grade 3 and 4 toxicities included leukopenia, thrombocytopenia and infection. Response rates were as follows: 21% partial response, 43% stable disease, and 36% progressive disease., Conclusion: Carboplatin and everolimus is a well-tolerated combination for heavily pre-treated metastatic breast cancer. Everolimus (10 mg/d) and carboplatin (AUC2 weekly) were defined as the MTD. This dose is currently being employed in an ongoing phase II trial.

BACKGROUND: Thrombotic microangiopathy (TMA) is defined as thrombocytopenia and microangiopathic hemolytic anemia. Cancer-associated TMA, a rare but fatal condition, seems an entity distinct from classical thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). PATIENTS AND METHODS: All patients with breast cancer-associated TMA treated at our institution between 2003 and 2008 were analyzed retrospectively. To elucidate pathophysiological mechanisms, we measured the serum activity of the metalloprotease ADAMTS13. RESULTS: 8 patients were identified. All showed bone marrow infiltration of breast cancer as well as thrombocytopenia, schistocytes, and hemolytic anemia. ADAMTS13 activity was mildly decreased in 4/6 patients (20-108%, normal range 30-120%), but none showed severely low levels as is characteristic of classical TTP. 6 patients were treated with anthracycline-containing fractionated chemotherapy, 5/6 patients experienced partial response. Overall survival was 13 months. Fractionated chemotherapy was well tolerated. CONCLUSIONS: Cancer-associated TMA has an underlying mechanism different from classical TTP. While bone marrow infiltration might be of major relevance, ADAMTS13 deficiency seems to be an epiphenomenon. Fractionated chemotherapy resulted in higher remission rates and comparatively long survival.

Background: Patients with synchronous metastastic breast cancer and intact primary tumor traditionally undergo systemic treatment. Surgical intervention at the primary site is typically reserved for palliation and often replaceable by radiation. Nevertheless, local surgery in metastatic breast cancer has become an issue of great controversy since retrospective studies published during the recent years suggested a slight benefit from an operative procedure. We evaluated the effect of surgery on long-term survival and progression-free survival in synchronous stage IV breast cancer., Methods: We retrospectively reviewed the records of all breast cancer patients treated at our institution between 1986 and 2007. Information recorded for each patient included age, tumor characteristics, metastasis characteristics, therapy, progression-free survival, and overall survival. Survival data were compared between surgical and nonsurgical patients., Results: 61 patients with synchronous metastastic breast cancer and intact primary tumor were analyzed. 26 patients (43%) received no primary site surgery and 35 (57%) patients had surgery. Overall survival and progression-free survival determined via the Kaplan-Meier method showed no significant difference between the surgery and the non-surgery group., Conclusion: In patients with metastatic breast cancer, the operation of the primary tumor did not influence overall survival or progression-free survival., (Copyright © 2011 S. Karger AG, Basel.)