178 results on '"Gerald Wulf"'
Search Results
2. Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe
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Enver Aydilek, Gerald Wulf, Friedrich Schwarz, Ulrike Bacher, Mathias Rummel, Olga Stiefel, Andrea Kerkhoff, Markus Maulhardt, Thomas Melchardt, Thomas Pabst, Georg Lenz, and Evgenii Shumilov
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compassionate use program ,mantle cell lymphoma ,outcomes ,pirtobrutinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Mantle cell lymphoma (MCL) is a type of B‐cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real‐world data are scarce. Methods In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). Results On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow‐up of 8.6 months, the mean duration of response (DOR), progression‐free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. Conclusions In summary, pirtobrutinib represented a safe and effective treatment option in a small real‐world population.
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- 2024
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3. Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease
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Halvard Bonig, Mareike Verbeek, Peter Herhaus, Krischan Braitsch, Gernot Beutel, Christoph Schmid, Nadine Müller, Gesine Bug, Michaela Döring, Arend von Stackelberg, Johanna Tischer, Francis Ayuk, Gerald Wulf, Udo Holtick, Lisa-Marie Pfeffermann, Bernd Jahrsdörfer, Hubert Schrezenmeier, Selim Kuci, Zyrafete Kuci, Anke Zens, Michael Tribanek, Robert Zeiser, Sabine Huenecke, and Peter Bader
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MSC-FFM ,Mesenchymal stromal cells ,Steroid-refractory ,Ruxolitinib-refractory ,Allogeneic haematopoietic stem cell transplantation ,Medicine - Abstract
Abstract Background Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. Methods We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children. Results The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months). Conclusion A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD.
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- 2023
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4. Correction: Real‑world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC‑FFM in ruxolitinib‑refractory acute graft‑versus‑host disease
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Halvard Bonig, Mareike Verbeek, Peter Herhaus, Krischan Braitsch, Gernot Beutel, Christoph Schmid, Nadine Müller, Gesine Bug, Michaela Döring, Arend von Stackelberg, Johanna Tischer, Francis Ayuk, Gerald Wulf, Udo Holtick, Lisa‑Marie Pfeffermann, Bernd Jahrsdörfer, Hubert Schrezenmeier, Selim Kuci, Zyrafete Kuci, Anke Zens, Michael Tribanek, Robert Zeiser, Sabine Huenecke, and Peter Bader
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Medicine - Published
- 2024
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5. Chimeric antigen receptor‐T cell therapy shows similar efficacy and toxicity in patients with diffuse large B‐cell lymphoma aged 70 and older compared to younger patients: A multicenter cohort study
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Philipp Berning, Evgenii Shumilov, Markus Maulhardt, Hristo Boyadzhiev, Andrea Kerkhoff, Simon Call, Christian Reicherts, Anna O. Saidy, Enver Aydilek, Michèle Hoffmann, Urban Novak, Michael Daskalakis, Norbert Schmitz, Matthias Stelljes, Gerald Wulf, Ulrike Bacher, Georg Lenz, and Thomas Pabst
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract CD19‐directed chimeric antigen receptor (CAR)‐T cell therapy has become a standard treatment for relapsed/refractory diffuse large B‐cell lymphoma (r/r DLBCL). While the benefits of CAR‐T cell treatment are clear in the general patient population, there remains a relative scarcity of real‐world evidence regarding its efficacy and toxicity in patients (pts) aged ≥70 years with DLBCL. We conducted a multicenter retrospective analysis including 172 r/r DLBCL pts with CAR‐T cell treatment, axicabtagene ciloleucel or tisagenlecleucel, between 2019 and 2023 at three tertiary centers. Pts were grouped by age at CAR‐T infusion (
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- 2024
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6. A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes
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Albert Rosenberger, Rachel E. Crossland, Ralf Dressel, Dieter Kube, Daniel Wolff, Gerald Wulf, Heike Bickeböller, Anne Dickinson, and Ernst Holler
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HSCT ,GvHD ,GWAS ,survival ,competing risks ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionData on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce.MethodsWe performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres.ResultsThe single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations.DiscussionThus, new genes were identified, potentially influencing the outcome of HSCT.
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- 2024
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7. Autologous-allogeneic versus autologous tandem stem cell transplantation and maintenance therapy with thalidomide for multiple myeloma patients under 60 years of age: a prospective, phase II study
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Nicolaus Kröger, Gerald Wulf, Ute Hegenbart, Andreas Burchert, Matthias Stelljes, Nico Gagelmann, Arne Brecht, Martin Kaufmann, Lutz Müller, Arnold Ganser, Dominik Wolf, Wolfgang Bethge, Martin Bornhäuser, Michael Kiehl, Eva-Maria Wagner, Christoph Schmid, Hans Christian Reinhardt, Guido Kobbe, Hans Salwender, Thomas Heinicke, Martin Kropff, Marion Heinzelmann, Francis Ayuk, Lorenz Trümper, Andreas Neubauer, Andreas Völp, Evgeny Kluychnikov, Stefan Schönland, and Christine Wolschke
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma is controversial. Between 2008 and 2014 a total of 217 multiple myeloma patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multicenter clinical trial to compare alloTSCT to autologous tandem transplantation (autoTSCT) followed by 2 years of maintenance therapy with thalidomide (100 mg/day) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent a second transplant (132 allogeneic, 46 autologous). PFS at 4 years after the second transplant was 47% (95% CI: 38-55%) for alloTSCT and 35% (95% CI: 21-49%) for autoTSCT (P=0.26). This difference increased to 22% at 8 years (P=0.10). The cumulative incidences of non-relapse mortality and of relapse at 4 years were 13% (95% CI: 8-20%) and 2% (95% CI: 0.3-2%) (P=0.044) and 40% (95% CI: 33-50%) and 63% (95% CI: 50-79%) (P=0.04) for alloTSCT and autoTSCT, respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (P=0.002). Four-year overall survival was 66% (95% CI: 57-73%) for alloTSCT and 66% (95% CI: 50-78%) for autoTSCT (P=0.91) and 8-year overall survival was 52% and 50% (P=0.87), respectively. In conclusion, alloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly. This study was registered with ClinicalTrials.gov (NCT00777998).
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- 2023
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8. Fatal Progression of Mutated TP53-Associated Clonal Hematopoiesis following Anti-CD19 CAR-T Cell Therapy
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Lea Naomi Eder, Danilo Martinovic, Paolo Mazzeo, Christina Ganster, Justin Hasenkamp, Julia Thomson, Arne Trummer, Detlef Haase, and Gerald Wulf
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clonal hematopoiesis ,CAR-T cell therapy ,clonal evolution ,therapy-related neoplasia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We present the case of a 64-year-old man diagnosed with large B-cell lymphoma who relapsed twice after standard-of-care therapy. Due to persisting cytopenia, Next generation sequencing analysis was performed, revealing a small TP53-mutated clone. As a third-line therapy, the patient was treated with CAR-T cells, which resulted in complete remission. However, this treatment also led to the expansion of the TP53-mutated clone and therapy-related myelodysplasia with a complex aberrant karyotype. This case may serve as a paradigmatic example of clonal hematopoietic progression in a patient undergoing CAR-T cell therapy, especially in the context of a TP53-mutated clone.
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- 2023
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9. Repeated Infusions of Brexucabtagene-autoleucel in Relapsed/Refractory Mantle Cell Lymphoma
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Enver Aydilek, Susanne Klein-Scory, Julia Thomson, Verena Nilius-Eliliwi, Deepak Vangala, Roland Schroers, Gerald Wulf, and Thomas Mika
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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10. Allogeneic hematopoietic stem cell transplantation in patients aged 60-79 years in Germany (1998-2018): a registry study
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Jan Frederic Weller, Claudia Lengerke, Jürgen Finke, Johannes Schetelig, Uwe Platzbecker, Hermann Einsele, Thomas Schroeder, Christoph Faul, Matthias Stelljes, Peter Dreger, Igor W. Blau, Gerald Wulf, Johanna Tischer, Christoph Scheid, Ahmet Elmaagacli, Helga Neidlinger, Sarah Flossdorf, Martin Bornhäuser, Wolfgang Bethge, Katharina Fleischhauer, Nicolaus Kröger, Liesbeth C. de Wreede, and Maximilian Christopeit
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Incidences of diseases treated with transplantation frequently peak at higher age. The contribution of age to total risk of transplantation has not been estimated amidst an aging society. We compare outcomes of 1,547 patients aged 70-79 years and 9,422 patients aged 60-69 years transplanted 1998-2018 for myeloid, lymphoid and further neoplasia in Germany. To quantify the contribution of population mortality to survival, we derive excess mortality based on a sex-, year- and agematched German population in a multistate model that incorporates relapse and graft-versus-host-disease (GvHD). Overall survival, relapse-free survival (RFS) and GvHD-free-relapse-free survival (GRFS) is inferior in patients aged 70-79 years, compared to patients aged 60-69 years, with 36% (95% Confidence Interval [CI]: 34-39%) versus 43% (41-44%), 32% (30- 35%) versus 36% (35-37%) and 23% (21-26%) versus 27% (26-28%) three years post-transplant (P1 year relapse-free is 6.7 (median, 95% CI: 4.5-9.4, 70-79 years) versus 9 (8.4-10.1, 60-69 years) years since landmark. Three years after RFS of one year, excess NRM is 14% (95% CI: 12-18%) in patients aged 70-79 versus 12% [11-13%] in patients aged 60-69, while population NRM is 7% (6-7%) versus 3% (3-3%). Mortality for reasons other than relapse, GvHD, or age is as high as 27% (24-29%) and 22% (22-23%) four years after transplantation. In conclusion, survival amongst older patients is adequate after allogeneic stem cell transplantation.
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- 2023
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11. S135: NEXT-GENERATION SEQUENCING-BASED MEASURABLE RESIDUAL DISEASE MONITORING IN ACUTE MYELOID LEUKEMIA WITH FLT3 INTERNAL TANDEM DUPLICATION TREATED WITH INTENSIVE CHEMOTHERAPY PLUS MIDOSTAURIN
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Frank G Rücker, Lars Bullinger, Sibylle Cocciardi, Sabrina Skambraks, Tamara J Luck, Daniela Weber, Isabelle Schneider, Andrea Corbacioglu, Verena I Gaidzik, Ekaterina Jahn, Nikolaus Jahn, Silke Kapp-Schwoerer, Anika Schrade, Frauke Theis, Walter Fiedler, Helmut R Salih, Gerald Wulf, Hans Salwender, Thomas Schroeder, Katharina S Götze, Thomas Kindler, Michael Lübbert, Richard F Schlenk, Felicitas Thol, Michael Heuser, Arnold Ganser, Hartmut Döhner, and Konstanze Döhner
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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12. S225: ALLOGENEIC STEM CELL TRANSPLANTATION FOR NK/T-CELL LYMPHOMA IN THE ERA OF ASPARAGINASE-BASED CHEMOTHERAPY: A RETROSPECTIVE ANALYSIS OF THE EBMT LYMPHOMA WORKING PARTY
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Philipp Berning, Norbert Schmitz, Maud Ngoya, Hevé Finel, Ariane Boumendil, Fengrong Wang, Xiaojun Huang, Olivier Hermine, Laure Philippe, Lucile Couronné, Arnaud Jaccard, Dai-Hong Liu, Depei Wu, Christian Reinhardt, Yves Chalandon, Eva Wagner-Drouet, MI Kwon, XI Zhang, Ben Carpenter, Ibrahim Yakoub-Agha, Gerald Wulf, Francisco Lopez Jimenez, Jaime Sanz, Hélène Labussiere Wallet, Avichai Shimoni, Peter Dreger, Anna Sureda, Won-Seog Kim, and Bertram Glass
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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13. P352: PROPHYLACTIC AND PREEMPTIVE USE OF DLI COMPARE FAVOURABLY TO THEIR THERAPEUTIC USE IN ADULT ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) – RESULTS OF A MULTICENTRE RETROSPECTIVE STUDY
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Maik Haupt, Nadja Jäkel, Maria Wachsmuth, Michael Stadler, Dietrich Beelen, Juergen Finke, Nael Alakel, Philipp Hemmati, Stefan Schönland, Wolfgang Bethge, Gerald Wulf, Daniel Wolff, Johanna Maria Tischer, Eva Wagner-Drouet, Anna Brandt, Nicolaus Kröger, Vladan Vucinic, Ben-Niklas Bärmann, Monika Brüggemann, Cora Gromann, Carsten Müller-Tidow, Nicola Gökbuget, and Lutz Mueller
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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14. Radiation and Dose-densification of R-CHOP in Aggressive B-cell Lymphoma With Intermediate Prognosis: The UNFOLDER Study
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Lorenz Thurner, Marita Ziepert, Christian Berdel, Christian Schmidt, Peter Borchmann, Dominic Kaddu-Mulindwa, Andreas Viardot, Mathias Witzens-Harig, Judith Dierlamm, Mathias Haenel, Bernd Metzner, Gerald Wulf, Eva Lengfelder, Ulrich B. Keller, Norbert Frickhofen, Maike Nickelsen, Tobias Gaska, Frank Griesinger, Rolf Mahlberg, Reinhard Marks, Ofer Shpilberg, Hans-Walter Lindemann, Martin Soekler, Ludwig Fischer von Weikersthal, Michael Kiehl, Eva Roemer, Martin Bentz, Beate Krammer-Steiner, Ralf Trappe, Peter de Nully Brown, Massimo Federico, Francesco Merli, Marianne Engelhard, Bertram Glass, Norbert Schmitz, Lorenz Truemper, Moritz Bewarder, Frank Hartmann, Niels Murawski, Stephan Stilgenbauer, Andreas Rosenwald, Bettina Altmann, Heinz Schmidberger, Jochen Fleckenstein, Markus Loeffler, Viola Poeschel, Gerhard Held, and on behalf of German Lymphoma Alliance (GLA)
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18–60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).
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- 2023
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15. Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial
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Gerhard Held, Lorenz Thurner, Viola Poeschel, German Ott, Christian Schmidt, Konstantinos Christofyllakis, Andreas Viardot, Peter Borchmann, Walburga Engel-Riedel, Norbert Frickhofen, Maike Nickelsen, Ofer Shpilberg, Mathias Witzens-Harig, Frank Griesinger, Beate Krammer-Steiner, Andreas Neubauer, Peter de Nully Brown, Massimo Federico, Bertram Glass, Norbert Schmitz, Gerald Wulf, Lorenz Truemper, Moritz Bewarder, Niels Murawski, Stephan Stilgenbauer, Andreas Rosenwald, Bettina Altmann, Marianne Engelhard, Heinz Schmidberger, Jochen Fleckenstein, Christian Berdel, Markus Loeffler, Marita Ziepert, and on behalf of the German Lymphoma Alliance (GLA)
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.
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- 2023
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16. 'SpezPat'- common advance directives versus disease-centred advance directives: a randomised controlled pilot study on the impact on physicians’ understanding of non-small cell lung cancer patients’ end-of-life decisions
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Julia Felicitas Leni Koenig, Thomas Asendorf, Alfred Simon, Annalen Bleckmann, Lorenz Truemper, Gerald Wulf, and Tobias R. Overbeck
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Advance directive ,Palliative care ,End-of-life decision making ,Prospective pilot study ,Special situations and conditions ,RC952-1245 - Abstract
Abstract Background The advance directive represents patients’ health care choices and fosters patients’ autonomy. Nevertheless, understanding patients’ wishes based on the information provided in advance directives remains a challenge for health care providers. Based on the ethical premises of positive obligation to autonomy, an advanced directive that is disease-centred and details potential problems and complications of the disease should help health care providers correctly understand patients’ wishes. To test this hypothesis, a pilot-study was conducted to investigate whether physicians could make the correct end-of-life decision for their patients when patients used a disease-centred advance directive compared to a common advance directive. Material and methods A randomised, controlled, prospective pilot study was designed that included patients with non-small cell lung cancer (NSCLC) stage VI from the Department of Haematology and Medical Oncology, University Medical Centre, Goettingen. Patients were randomised into intervention and control groups. The control group received a common advance directive, and the intervention group received a disease-centred advance directive. Both groups filled out their advance directives and returned them. Subsequently, patients were asked to complete nine medical scenarios with different treatment decisions. For each scenario the patients had to decide whether they wanted to receive treatment on a 5-point Likert scale. Four physicians were given the same scenarios and asked to decide on the treatment according to the patients’ wishes as stated in their advance directives. The answers by patients and physicians were then compared to establish whether physicians had made the correct assumptions. Results Recruitment was stopped prior to reaching anticipated sample target. 15 patients with stage IV NSCLC completed the study, 9 patients were randomised into the control group and 6 patients in the intervention group. A total of 135 decisions were evaluated. The concordance between physicians’ and patients’ answers, was 0.83 (95%-CI 0.71–0.91) in the intervention group, compared to 0.60 (95%-CI 0.48–0.70) in the control group, and the difference between the two groups was statistically significant (p = 0.005). Conclusion This pilot study shows that disease-centred advance directives help physicians understand their NSCLC patients’ wishes more precisely and make treatment choices according to these wishes. Trial registration The study is registered at the German Clinical Trial Register (no. DRKS00017580, registration date 27/08/2019).
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- 2022
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17. Optimizing the structure of interdisciplinary tumor boards for effective cancer care
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Friederike Braulke, Kathrin Kober, Andreas Arndt, Maximilian Papendick, Arne Strauss, Christof Maria Kramm, Kai-Martin Thoms, Alexander König, Jochen Gaedcke, Julia Gallwas, Svenja Wulf, Christoph Szuszies, Gerald Wulf, Ralph Rödel, Susanne Wolfer, Vesna Malinova, Tobias R. Overbeck, Marc Hinterthaner, Joachim Lotz, Friedemann Nauck, Marielle Ernst, Christine Stadelmann, Philipp Ströbel, Volker Ellenrieder, Thomas Asendorf, and Stefan Rieken
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multi-professional tumor boards ,radiology ,pathology ,specialized palliative care ,radio-oncology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionMulti-professional interdisciplinary tumor boards (ITB) are essential institutions to discuss all newly diagnosed, relapsed or complex cancer patients in a team of specialists to find an optimal cancer care plan for each individual patient with regard to national and international clinical practice guidelines, patient´s preference and comorbidities. In a high-volume cancer center, entity-specific ITBs take place at least once a week discussing a large number of patients. To a high level of expertise and dedication, this also requires an enormous amount of time for physicians, cancer specialists and administrative support colleagues, especially for radiologists, pathologists, medical oncologists and radiation oncologists, who must attend all cancer-specific boards according to certification requirements.MethodsIn this 15-month prospective German single-center analysis, we examined the established structures of 12 different cancer-specific ITBs at the certified Oncology Center and demonstrate tools helping to optimize processes before, during and after the boards for optimal, time-saving procedures.ResultsBy changing pathways, introducing revised registration protocols and new digital supports we could show that the workload of preparation by radiologists and pathologists could be reduced significantly by 22.9% (p=
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- 2023
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18. Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT
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Alexandros Spyridonidis, Myriam Labopin, Bipin Savani, Sebastian Giebel, Gesine Bug, Stefan Schönland, Nicolaus Kröger, Matthias Stelljes, Thomas Schroeder, Andrew McDonald, Igor-Wolfgang Blau, Martin Bornhäuser, Montse Rovira, Wolfgang Bethge, Andreas Neubauer, Arnold Ganser, Jean Henri Bourhis, Matthias Edinger, Bruno Lioure, Gerald Wulf, Kerstin Schäfer-Eckart, Mutlu Arat, Zinaida Peric, Christoph Schmid, Ali Bazarbachi, Fabio Ciceri, Arnon Nagler, and Mohamad Mohty
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P
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- 2023
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19. Quantification of cell-free DNAfor the analysis of CD19-CAR-T cells during lymphoma treatment
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Thomas Mika, Julia Thomson, Verena Nilius-Eliliwi, Deepak Vangala, Alexander Baraniskin, Gerald Wulf, Susanne Klein-Scory, and Roland Schroers
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CD19-directed chimeric antigen receptor T cells ,CAR-T cells ,digital-droplet PCR (ddPCR) ,liquid biopsy ,cell-free DNA ,lymphoma ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Chimeric antigen receptor (CAR)-T cells are increasingly used for the treatment of hematologic malignancies. Treatment success relies highly upon sufficient expansion of CAR-T effector cells. Accordingly, longitudinal quantification of CAR-T cells during therapy is clinically important. Techniques to quantify CAR-T cells in patient blood samples are based on flow cytometry and PCR. However, cellular kinetics of CAR-T cells are very complex and under current investigation. In this study, feasibility of CAR-T cell quantification by cell-free DNA (cfDNA) was analyzed. cfDNA isolated from 74 blood samples of 12 patients during lymphoma treatment with the anti-CD19 CAR-T cell product axicabtagene ciloleucel (axi-cel) were analyzed. Concentrations of cfDNA specific for the CAR-T gene construct (cfCAR-DNA) and a reference gene were quantified by a newly designed digital-droplet PCR (ddPCR) assay. Detection and quantification of cfCAR-DNA was feasible and reliable for all patients included. Relative quantification of cfCAR-DNA compared to a reference gene, suitable for genomic DNA analysis, was heterogeneous in treatment responders and non-responders. In contrast, parallel analyses of cfCAR-DNA and reference cfDNA in a patient-specific approach gave insight into active lymphoma killing and treatment responses. In summary, plasma cfDNA determination in lymphoma patients is a promising tool for future clinical decision making.
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- 2021
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20. First-line Treatment With Bendamustine and Rituximab for Old and Frail Patients With Aggressive Lymphoma: Results of the B-R-ENDA Trial
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Friederike Braulke, Florian Zettl, Marita Ziepert, Andreas Viardot, Christoph Kahl, Gabriele Prange-Krex, Agnieszka Korfel, Martin Dreyling, Alexander Bott, Ulrich Wedding, Dietmar Reichert, Maike de Wit, Frank Hartmann, Viola Poeschel, Norbert Schmitz, Mathias Witzens-Harig, Wolfram Klapper, Andreas Rosenwald, Gerald Wulf, Bettina Altmann, and Lorenz Trümper
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
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.
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- 2022
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21. HLA-DRB3/4/5 Matching Improves Outcome of Unrelated Hematopoietic Stem Cell Transplantation
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Chrysanthi Tsamadou, Daphne Engelhardt, Uwe Platzbecker, Elisa Sala, Thomas Valerius, Eva Wagner-Drouet, Gerald Wulf, Nicolaus Kröger, Niels Murawski, Hermann Einsele, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Martin Kaufmann, Mareike Dürholt, Bernd Hertenstein, Stefan Klein, Mark Ringhoffer, Sandra Frank, Christine Neuchel, Hubert Schrezenmeier, Joannis Mytilineos, and Daniel Fuerst
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HLA-DRB3 ,HLA-DRB4 ,HLA-DRB5 ,HLA-DRB3/4/5 ,unrelated hematopoietic stem cell transplantation (uHSCT) ,HLA-matched ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5 mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future.
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- 2021
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22. Rituximab Maintenance Versus Observation After Immunochemotherapy (R-CHOP, R-MCP, and R-FCM) in Untreated Follicular Lymphoma Patients: A Randomized Trial of the Ostdeutsche Studiengruppe Hämatologie und Onkologie and the German Low-Grade Lymphoma Study Group
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Carsten Hirt, Eva Hoster, Michael Unterhalt, Mathias Hänel, Gabriele Prange-Krex, Roswitha Forstpointner, Axel Florschütz, Ullrich Graeven, Norbert Frickhofen, Gerald Wulf, Eva Lengfelder, Christian Lerchenmüller, Rudolf Schlag, Judith Dierlamm, Ludwig Fischer von Weikersthal, Asima Ahmed, Hanns-Detlev Harich, Andreas Rosenwald, Wolfram Klapper, Martin Dreyling, Wolfgang Hiddemann, and Michael Herold
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The German study groups, the German Low-Grade Lymphoma Study Group (GLSG) and Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO), initiated in 2007 a double randomized trial to investigate efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment in the first-line follicular lymphoma. Previously untreated patients with stage II–IV follicular lymphoma in need of therapy were randomized to receive 6 cycles of R-CHOP, R-MCP, or R-FCM. Responding patients were subsequently randomized to 2 years rituximab maintenance or observation, stratified by type of immunochemotherapy, quality of remission, and Follicular Lymphoma International Prognostic Index (FLIPI). Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24–86), and (FLIPI) was low in 13%, intermediate in 28%, and high in 60%. High and comparable overall response rates were observed after R-CHOP (88%), R-MCP (89%), and R-FCM (91%). Rituximab maintenance substantially prolonged progression-free survival (PFS) in comparison to observation in remission (hazard ratio 0.39, P = 0.0064). In the rituximab maintenance group, the 3-year PFS was 89% compared with 69% in the observation group. No differences in overall survival were observed for maintenance vs. observation (hazard ratio 1.04, 95% confidence interval 0.32–3.43, P = 0.95). In this randomized trial, 2 years of rituximab maintenance was associated with significantly prolonged PFS in comparison to observation after response to first-line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the PRIMA trial results. (Clinical Trial EudraCT Number: 2005-005473-29, 2006-09-26)
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- 2021
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23. Clinical Post-SARS-CoV-2 Infection Scenarios in Vaccinated and Non-Vaccinated Cancer Patients in Three German Cancer Centers: A Retrospective Analysis
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Evgenii Shumilov, Lena Aperdannier, Nicole Schmidt, Christoph Szuszies, Albrecht Neesse, Petra Hoffknecht, Cyrus Khandanpour, Jan-Henrik Mikesch, Matthias Stelljes, Göran Ramin Boeckel, Phil-Robin Tepasse, Lea Reitnauer, Raphael Koch, Justin Hasenkamp, Ulrike Bacher, Simone Scheithauer, Lorenz Trümper, Norbert Schmitz, Gerald Wulf, Andrea Kerkhoff, Georg Lenz, Carolin Krekeler, and Annalen Bleckmann
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SARS-CoV-2 ,COVID-19 ,COVID-19 vaccination ,cancer patients ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
COVID-19 vaccines have become an integral element in the protection of cancer patients against SARS-CoV-2. To date, there are no direct comparisons of the course of COVID-19 infection in cancer patients between the pre- and post-vaccine era. We analyzed SARS-CoV-2 infections and their impact on cancer in COVID-19 vaccinated and non-vaccinated patients from three German cancer centers. Overall, 133 patients with SARS-CoV-2 were enrolled in pre- and post-vaccine eras: 84 non-vaccinated and 49 vaccinated, respectively. A mild course of COVID-19 was documented more frequently in vaccinated patients (49% vs. 29%), while the frequency of severe and critical courses occurred in approximately one-half of the non-vaccinated patients (22% vs. 42%, p = 0.023). Particularly, patients with hematologic neoplasms benefited from vaccination in this context (p = 0.031). Admissions to intermediate- and intensive-care units and the necessity of non-invasive and invasive respiratory support were reduced by 71% and 50% among vaccinated patients, respectively. The median length of admission was 11 days for non-vaccinated and 5 days for vaccinated patients (p = 0.002). COVID-19 mortality was reduced by 83% in vaccinated patients (p = 0.046). Finally, the median time from SARS-CoV-2 infection to restarting cancer therapy was 12 and 26 days among vaccinated and non-vaccinated groups, respectively (p = 0.002). Although this study does not have enough power to perform multivariate analyses to account for confounders, it provides data on COVID-19 in non-vaccinated and vaccinated cancer patients and illustrates the potential benefits of COVID-19 vaccines for these patients.
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- 2022
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24. A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a DNA-based CMV vaccine, in seropositive allogeneic haematopoietic cell transplant recipients
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Per Ljungman, Arancha Bermudez, Aaron C. Logan, Mohamed A. Kharfan-Dabaja, Patrice Chevallier, Rodrigo Martino, Gerald Wulf, Dominik Selleslag, Kazuhiko Kakihana, Amelia Langston, Dong-Gun Lee, Carlos Solano, Shinichiro Okamoto, Larry R. Smith, Michael Boeckh, John R. Wingard, Beth Cywin, Christine Fredericks, Christopher Lademacher, Xuegong Wang, James Young, and Johan Maertens
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Medicine (General) ,R5-920 - Abstract
Background: Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients. Methods: In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting). Findings: Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 (n = 246) or placebo (n = 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% (n = 87) with ASP0113 and 30•2% (n = 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85; p = 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 (p = 0.027). Interpretation: ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups. Funding: Astellas Pharma Global Development, Inc .
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- 2021
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25. The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis
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Daphne Mytilineos, Chrysanthi Tsamadou, Christine Neuchel, Uwe Platzbecker, Donald Bunjes, Natalie Schub, Eva Wagner-Drouet, Gerald Wulf, Nicolaus Kröger, Niels Murawski, Hermann Einsele, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Martin Kaufmann, Mareike Dürholt, Bernd Hertenstein, Stefan Klein, Mark Ringhoffer, Carlheinz R. Mueller, Sandra Frank, Hubert Schrezenmeier, Daniel Fuerst, and Joannis Mytilineos
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stem cell transplantation ,graft-versus-host-disease ,HLA-DPB1 ,HLA-DPB1 expression ,HLA-DPB1-permissiveness ,Immunologic diseases. Allergy ,RC581-607 - Abstract
T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.
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- 2021
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26. Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation
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Wener Li, Michael Stauske, Xiaojing Luo, Stefan Wagner, Meike Vollrath, Carola S. Mehnert, Mario Schubert, Lukas Cyganek, Simin Chen, Sayed-Mohammad Hasheminasab, Gerald Wulf, Ali El-Armouche, Lars S. Maier, Gerd Hasenfuss, and Kaomei Guan
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Brugada syndrome ,disease modeling ,induced pluripotent stem cells ,SCN5A mutation ,depolarization ,repolarization ,Biology (General) ,QH301-705.5 - Abstract
Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of INa density, a 69.5% reduction of NaV1.5 expression, and the impaired localization of NaV1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The Ito in BrS-CMs was significantly augmented, and the ICaL window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of Ito in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.
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- 2020
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27. Association of uric acid levels before start of conditioning with mortality after allogeneic hematopoietic stem cell transplantation – a prospective, non-interventional study of the EBMT Transplant Complication Working Party
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Olaf Penack, Christophe Peczynski, Steffie van der Werf, Jürgen Finke, Arnold Ganser, Helene Schoemans, Jiri Pavlu, Riitta Niittyvuopio, Wilfried Schroyens, Leylagül Kaynar, Igor W. Blau, Walter van der Velden, Jorge Sierra, Agostino Cortelezzi, Gerald Wulf, Pascal Turlure, Montserat Rovira, Zubeydenur Ozkurt, Maria J. Pascual-Cascon, Maria C. Moreira, Johannes Clausen, Hildegard Greinix, Rafael F. Duarte, and Grzegorz W. Basak
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline comorbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0–2.4, P=0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7–4.7, P
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- 2020
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28. Association of Country-Specific Socioeconomic Factors With Survival of Patients Who Experience Severe Classic Acute Graft-vs.-Host Disease After Allogeneic Hematopoietic Cell Transplantation. An Analysis From the Transplant Complications Working Party of the EBMT
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Andrzej Frankiewicz, Christophe Peczynski, Sebastian Giebel, Alenca Harrington, Gerard Socié, Dietger Niederwieser, Christoph Scheid, Martin Bornhäuser, Nicolaus Kröger, Ahmet Elmaagacli, Boris Afanasyev, Peter Dreger, Claudia Rössig, Didier Blaise, Christian Kratz, Ibrahim Yakoub-Agha, Bernhard Kremens, Charlotte Marie Niemeyer, Gerald Wulf, Igor Blau, Olaf Penack, Hildegard Greinix, and Grzegorz W. Basak
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health care expenditure ,human development index ,hematopoietic cell transplantation ,acute graft-vs.-host disease ,transplant-related mortality ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings (n = 1,328) or unrelated donors (n = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, p = 0.04), lower HCE as % of Gross Domestic Product per capita (p = 0.003) and lower values of the Human Development Index (p = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, p = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, p = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, p = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD.
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- 2020
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29. Digital-Droplet PCR for Quantification of CD19-Directed CAR T-Cells
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Thomas Mika, Abdelouahid Maghnouj, Susanne Klein-Scory, Swetlana Ladigan-Badura, Alexander Baraniskin, Julia Thomson, Justin Hasenkamp, Stephan A. Hahn, Gerald Wulf, and Roland Schroers
- Subjects
CD19-directed chimeric antigen receptor (CAR) T-cells ,axicabtagene ciloleucel ,aggressive lymphoma ,digital-droplet PCR (ddPCR) ,flow cytometry (FCM) ,immunotherapy ,Biology (General) ,QH301-705.5 - Abstract
CD19-directed CAR-T-cells (CD19-CAR) have demonstrated remarkable clinical results in patients suffering from refractory or relapsed lymphoma and acute lymphoblastic leukemia. In order to further optimize follow-up, to explain treatment failure, and to control adverse events biomarkers for monitoring of response are urgently needed. Peak expansion and persistence are correlated with response rates and severity of side effects. However, no standardized method or commercially assay for CD19-CAR measurement is established yet. In this study, two primer-probe assays for digital-droplet PCR (ddPCR) were designed and subsequently explored on 54 samples collected from seven patients after CD19-CAR treatment with axi-cel over time. Detection and quantification of CAR-T-cells were feasible and reliable for all patients included. Peak expansion measured with our assay significantly correlated with the grade of neurologic adverse events but not with cytokine release syndrome. All patients with loss of CAR-signal eventually had disease progression. In summary, our novel assay allows monitoring of CAR-T-cells in vivo and may add to safety and efficacy of CAR-T treatment.
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- 2020
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30. Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party
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Olaf Penack, Christophe Peczynski, Steffie van der Werf, Jürgen Finke, Arnold Ganser, Helene Schoemans, Jiri Pavlu, Riitta Niittyvuopio, Wilfried Schroyens, Leylagül Kaynar, Igor W. Blau, Walter J. F. M. van der Velden, Jorge Sierra, Agostino Cortelezzi, Gerald Wulf, Pascal Turlure, Montserrat Rovira, Zubeydenur Ozkurt, Maria J. Pascual-Cascon, Maria C. Moreira, Johannes Clausen, Hildegard Greinix, Rafael F. Duarte, and Grzegorz W. Basak
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transplantation ,stem cell ,immunology ,biomarker ,iron metabolism ,ferritin ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 μg/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5–4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6–3.8, p < 0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2–3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5–6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6–9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.
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- 2020
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31. A 70% cut-off for MYC protein expression in diffuse large B cell lymphoma identifies a high-risk group of patients
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Marita Ziepert, Stefano Lazzi, Raffaella Santi, Federica Vergoni, Massimo Granai, Virginia Mancini, Annette Staiger, Heike Horn, Markus Löffler, Viola Pöschel, Gerhald Held, Gerald Wulf, Lorenz H. Trümper, Norbert Schmitz, Andreas Rosenwald, Elena Sabattini, Kikkeri N. Naresh, Harald Stein, German Ott, and Lorenzo Leoncini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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32. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies
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Tim Ripperger, Winfried Hofmann, Jan C. Koch, Katayoon Shirneshan, Detlef Haase, Gerald Wulf, Peter R. Issing, Matthias Karnebogen, Gunnar Schmidt, Bernd Auber, Brigitte Schlegelberger, Thomas Illig, Birgit Zirn, and Doris Steinemann
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2018
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33. Increased age-associated mortality risk in HLA-mismatched hematopoietic stem cell transplantation
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Daniel Fürst, Dietger Niederwieser, Donald Bunjes, Eva M. Wagner, Martin Gramatzki, Gerald Wulf, Carlheinz R. Müller, Christine Neuchel, Chrysanthi Tsamadou, Hubert Schrezenmeier, and Joannis Mytilineos
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We investigated a possible interaction between age-associated risk and HLA-mismatch associated risk on prognosis in different age categories of recipients of unrelated hematopoietic stem cell transplants (HSCT) (n=3019). Patients over 55 years of age transplanted with 8/10 donors showed a mortality risk of 2.27 (CI 1.70–3.03, P
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- 2017
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34. Impact of Donor Activating KIR Genes on HSCT Outcome in C1-Ligand Negative Myeloid Disease Patients Transplanted with Unrelated Donors-A Retrospective Study.
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Christine Neuchel, Daniel Fürst, Dietger Niederwieser, Donald Bunjes, Chrysanthi Tsamadou, Gerald Wulf, Michael Pfreundschuh, Eva Wagner, Gernot Stuhler, Hermann Einsele, Hubert Schrezenmeier, and Joannis Mytilineos
- Subjects
Medicine ,Science - Abstract
Natural Killer cells (NK) are lymphocytes with the potential to recognize and lyse cells which escaped T-cell mediated lysis due to their aberrant HLA expression profiles. Killer cell immunoglobulin-like receptors (KIR) influence NK-cell activity by mediation of activating or inhibitory signals upon interaction with HLA-C (C1, C2) ligands. Therefore, absence of ligands for donor inhibitory KIRs following hematopoietic stem cell transplantation (HSCT) may have an influence on its outcome. Previous studies showed that C1 negative patients have a decreased HSCT outcome. Our study, based on a cohort of 200 C1-negative patients, confirmed these findings for the endpoints: overall survival (OS: HR = 1.41, CI = 1.14-1.74, p = 0.0012), disease free survival (DFS: HR = 1.27, CI = 1.05-1.53, p = 0.015), treatment related mortality (TRM: HR = 1.41, CI = 1.01-1.96, p = 0.04), and relapse incidence (RI: HR = 1.33, CI = 1.01-1.75, p = 0.04) all being inferior when compared to C1-positive patients (n = 1246). Subsequent analysis showed that these findings applied for patients with myeloid malignancies but not for patients with lymphoproliferative diseases (OS: myeloid: HR = 1.51, CI = 1.15-1.99, p = 0.003; lymphoblastic: HR = 1.26, CI = 0.91-1.75, p = 0.16; DFS: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21; RI: myeloid: HR = 1.31, CI = 1.01-1.70, p = 0.04; lymphoblastic: HR = 1.21, CI = 0.90-1.61, p = 0.21). Interestingly, within the C1-negative patient group, transplantation with KIR2DS2 resulted in better OS (9/10 matched: HR = 0.24, CI = 0.08-0.67, p = 0.007) as well as DFS (9/10 matched: HR = 0,26, CI = 0.11-0.60, p = 0.002), and transplantation with KIR2DS1 positive donors was associated with a decreased RI (HR = 0.30, CI = 0.13-0.69, p = 0.005). TRM was increased when the donor was positive for KIR2DS1 (HR = 2.61, CI = 1.26-5.41, p = 0.001). Our findings suggest that inclusion of KIR2DS1/2/5 and KIR3DS1-genotyping in the unrelated donor search algorithm of C1-ligand negative patients with myeloid malignancies may prove to be of clinical relevance.
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- 2017
- Full Text
- View/download PDF
35. A lurking threat: transfer of peanut allergy through peripheral blood stem cell transplantation
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Birka Brauns, Michael P. Schön, Gerald Wulf, and Martin Mempel
- Subjects
Immunologic diseases. Allergy ,RC581-607 - Abstract
Background There exist several reports of atopy and allergen-specific IgE-mediated hypersensitivity transferred by bone marrow transplantation, and it has been concluded that the transfer of allergic reactivity results from adoptive transfer of IgE-producing donor-derived B- and/or plasma cells. To the best of our knowledge we report the first case of peanut allergy after PBSCT.Case presentation A 55-year-old anciently non allergic man with secondary acute myeloid leukemia (AML) received an allogeneic peripheral blood stem cell transplantation from a matched unrelated donor following reduced-intensity conditioning. On day 32 after PBSCT, while still on prophylactic systemic immunosuppression, the patient noticed a first episode of angioedema with swelling of the nasal and oral mucosa 30 min after consuming peanut puffs. In a second episode, eight months after PBSCT, he again developed angioedema, generalized pruritus and nausea within minutes after eating biscuits containing hazelnut and peanut. Moreover, after topical application of a peanut oil-containing ointment, the patient experienced facial erythema and angioedema. Nine months after PBSCT an evaluation for peanut allergy revealed a highly increased specific IgE to peanut of 75.9 kU/l. Accordingly, skin prick tests for peanut extract were also positive. In consequence, the patient was counseled to strictly avoid peanut-related products, and provided with an emergency set. No adverse allergic events have occurred since for an observation time of 15 months after PBSCT. The stem cell donor was contacted and confirmed intolerance to peanuts. His specific serum IgE pattern nine month after PBSCT harvest was analysed and showed similar sensitization profiles compared to those of the transplant recipient.Conclusions Because of the close temporal association between the onset of allergic symptoms in the PBSC recipient it is reasonable to assume that the acquired peanut allergy had been transferred from the donor to the recipient by the PBSC graft. Keywords: Peanut allergy, Stem cell transplantation, Allergy transfer, IgE-mediated hypersensitivity
- Published
- 2016
- Full Text
- View/download PDF
36. Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
- Author
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Jason R. Westin, Frederick L. Locke, Michael Dickinson, Armin Ghobadi, Mahmoud Elsawy, Tom van Meerten, David B. Miklos, Matthew L. Ulrickson, Miguel-Angel Perales, Umar Farooq, Luciano Wannesson, Lori Leslie, Marie José Kersten, Caron A. Jacobson, John M. Pagel, Gerald Wulf, Patrick Johnston, Aaron P. Rapoport, Linqiu Du, Saran Vardhanabhuti, Simone Filosto, Jina Shah, Julia T. Snider, Paul Cheng, Christina To, Olalekan O. Oluwole, and Anna Sureda
- Subjects
Cancer Research ,Oncology - Abstract
Purpose: Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7. Patients and Methods: Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs). Results: Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and Conclusions: Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
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- 2023
37. Gemtuzumab Ozogamicin Plus Intensive Chemotherapy for Patients with NPM1-Mutated Acute Myeloid Leukemia
- Author
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Hartmut Döhner, Daniela Weber, Julia Krzykalla, Walter Fiedler, Michael W.M. Kühn, Thomas Schroeder, Karin Mayer, Michael Lübbert, Mohammad Wattad, Katharina Götze, Lars Fransecky, Elisabeth Koller, Gerald Wulf, Jan Schleicher, Mark Ringhoffer, Richard Greil, Bernd Hertenstein, Jürgen Krauter, Uwe M. Martens, David Nachbaur, Maisun Abu Samra, Sigrid Machherndl-Spandl, Nadezda Basara, Claudia Leis, Anika Schrade, Silke Kapp-Schwoerer, Lars Bullinger, Felicitas R. Thol, Michael Heuser, Peter Paschka, Verena I. Gaidzik, Maral Saadati, Axel Benner, Richard F. Schlenk, Konstanze Döhner, and Arnold Ganser
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
38. Midostaurin plus intensive chemotherapy for younger and older patients with AML and FLT3 internal tandem duplications
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Hartmut Döhner, Daniela Weber, Julia Krzykalla, Walter Fiedler, Gerald Wulf, Helmut Salih, Michael Lübbert, Michael W. M. Kühn, Thomas Schroeder, Hans Salwender, Katharina Götze, Jörg Westermann, Lars Fransecky, Karin Mayer, Bernd Hertenstein, Mark Ringhoffer, Hans-Joachim Tischler, Sigrid Machherndl-Spandl, Anika Schrade, Peter Paschka, Verena I. Gaidzik, Frauke Theis, Felicitas Thol, Michael Heuser, Richard F. Schlenk, Lars Bullinger, Maral Saadati, Axel Benner, Richard Larson, Richard Stone, Konstanze Döhner, and Arnold Ganser
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Adult ,Cancer Research ,Leukemia, Myeloid, Acute ,Young Adult ,Adolescent ,fms-Like Tyrosine Kinase 3 ,Hematopoietic Stem Cell Transplantation ,Humans ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Staurosporine ,Aged - Abstract
We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.
- Published
- 2022
39. Higher risk for chronic graft‐versus‐host disease ( <scp>GvHD</scp> ) in <scp>HLA‐G</scp> mismatched transplants following allogeneic hematopoietic stem cell transplantation: A retrospective study
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Christine Neuchel, Sowmya Gowdavally, Chrysanthi Tsamadou, Uwe Platzbecker, Elisa Sala, Eva Wagner‐Drouet, Thomas Valerius, Nicolaus Kröger, Gerald Wulf, Hermann Einsele, Lorenz Thurner, Kerstin Schaefer‐Eckart, Sebastian Freitag, Jochen Casper, Mareike Dürholt, Martin Kaufmann, Bernd Hertenstein, Stefan Klein, Mark Ringhoffer, Sandra Frank, Elisa Maria Amann, Immanuel Rode, Hubert Schrezenmeier, Joannis Mytilineos, and Daniel Fürst
- Subjects
HLA-G Antigens ,Leukemia, Myeloid, Acute ,Immunology ,Hematopoietic Stem Cell Transplantation ,Genetics ,Graft vs Host Disease ,Humans ,Immunology and Allergy ,Alleles ,Retrospective Studies - Abstract
Graft-versus-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA-class Ib molecule HLA-G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo-HSCT setting, HLA-G mismatches may negatively impact the HLA-G-mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA-G on host cells by the immune cells of the donor.In order to explore this hypothesis, we investigated the impact of HLA-G mismatching in 2.083 10/10 matched high resolution HLA-typed allo-HSCT transplants.We found that the risk of chronic GvHD was significantly higher in HLA-G-mismatched transplant cases as compared with the HLA-G-matched control group (HR: 1.46, 95%CI = 1.11-1.91, p = 0.006). Sub-analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39-2.57, p 0.001) but not the HvG direction (HR: 1.01, 95%CI = 0.63-1.63, p = 0.967). In addition, the negative impact of HLA-G mismatching on chronic GvHD was only significant in younger patients (30y HR: 3.02, 95%CI = 1.25-7.28, p = 0.014;29y HR: 1.28, 95%CI = 0.94-1.72, p = 0.113).Our results indicate that HLA-G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible.
- Published
- 2022
40. Donor genetic determinant of thymopoiesis rs2204985 impacts clinical outcome after single HLA mismatched hematopoietic stem cell transplantation
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Chrysanthi Tsamadou, Sowmya Gowdavally, Uwe Platzbecker, Elisa Sala, Thomas Valerius, Eva Wagner-Drouet, Gerald Wulf, Nicolaus Kröger, Niels Murawski, Hermann Einsele, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Martin Kaufmann, Mareike Dürholt, Bernd Hertenstein, Stefan Klein, Mark Ringhoffer, Sandra Frank, Christine Neuchel, Immanuel Rode, Hubert Schrezenmeier, Joannis Mytilineos, and Daniel Fuerst
- Subjects
Adult ,Transplantation ,Receptors, Antigen, T-Cell, alpha-beta ,Haematopoietic stem cells ,Hematopoietic Stem Cell Transplantation ,Stem cell transplantation ,Graft vs Host Disease ,Receptors, Antigen, T-Cell, gamma-delta ,Hematology ,Thrombopoiesis ,Stem-cell research ,Tissue donors ,HLA Antigens ,Blutstammzelle ,Humans ,ddc:610 ,Neoplasm Recurrence, Local ,Unrelated Donors ,DDC 610 / Medicine & health ,Hematopoietic stem cells ,Periphere Stammzellentransplantation ,Retrospective Studies - Abstract
A common genetic variant within the T cell receptor alpha (TCRA)-T cell receptor delta (TCRD) locus (rs2204985) has been recently found to associate with thymic function. Aim of this study was to investigate the potential impact of donor rs2204985 genotype on patient’s outcome after unrelated hematopoietic stem cell transplantation (uHSCT). 2016 adult patients were retrospectively analyzed. rs2204985 genotyping was performed by next generation sequencing, p < 0.05 was considered significant and donor rs2204985 GG/AG genotypes were set as reference vs. the AA genotype. Multivariate analysis of the combined cohort regarding the impact of donor’s rs2204985 genotype indicated different risk estimates in 10/10 and 9/10 HLA matched transplantations. A subanalysis on account of HLA incompatibility revealed that donor AA genotype in single HLA mismatched cases (n = 624) associated with significantly inferior overall- (HR: 1.48, p = 0.003) and disease-free survival (HR: 1.50, p = 0.001). This effect was driven by a combined higher risk of relapse incidence (HR: 1.40, p = 0.026) and non-relapse mortality (HR: 1.38, p = 0.042). This is the first study to explore the role of rs2204985 in a clinical uHSCT setting. Our data suggest that donor rs2204985 AA genotype in combination with single HLA mismatches may adversely impact post-HSCT outcome and should thus be avoided., publishedVersion
- Published
- 2022
41. Supplementary Figure S5 from Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
- Author
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Anna Sureda, Olalekan O. Oluwole, Christina To, Paul Cheng, Julia T. Snider, Jina Shah, Simone Filosto, Saran Vardhanabhuti, Linqiu Du, Aaron P. Rapoport, Patrick Johnston, Gerald Wulf, John M. Pagel, Caron A. Jacobson, Marie José Kersten, Lori Leslie, Luciano Wannesson, Umar Farooq, Miguel-Angel Perales, Matthew L. Ulrickson, David B. Miklos, Tom van Meerten, Mahmoud Elsawy, Armin Ghobadi, Michael Dickinson, Frederick L. Locke, and Jason R. Westin
- Abstract
CAR T-cell levels in patients ≥65 years
- Published
- 2023
42. Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis
- Author
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Philipp Berning, Norbert Schmitz, Maud Ngoya, Hervé Finel, Ariane Boumendil, Fengrong Wang, Xiao-Jun Huang, Olivier Hermine, Laure Philippe, Lucile Couronné, Arnaud Jaccard, Daihong Liu, Depei Wu, Hans Christian Reinhardt, Yves Chalandon, Eva Wagner-Drouet, Mi Kwon, Xi Zhang, Ben Carpenter, Ibrahim Yakoub-Agha, Gerald Wulf, Javier López-Jiménez, Jaime Sanz, Hélène Labussière-Wallet, Avichai Shimoni, Peter Dreger, Anna Sureda, Won Seog Kim, and Bertram Glass
- Subjects
Cancer Research ,Oncology ,Medizin ,Hematology - Abstract
Natural killer/T-cell lymphomas (NKTCL) represent rare and aggressive lymphoid malignancies. Patients (pts) with relapsed/refractory disease after Asparaginase (ASPA)-based chemotherapy have a dismal prognosis. To better define the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), we conducted a retrospective analysis of data shared with the European Society for Blood and Marrow Transplantation (EBMT) and cooperating Asian centers. We identified 135 pts who received allo-HSCT between 2010 and 2020. Median age was 43.4 years at allo-HSCT, 68.1% were male. Ninety-seven pts (71.9 %) were European, 38 pts (28.1%) Asian. High Prognostic Index for NKTCL (PINK) scores were reported for 44.4%; 76.3% had >1 treatment, 20.7% previous auto-HSCT, and 74.1% ASPA-containing regimens prior to allo-HSCT. Most (79.3%) pts were transplanted in CR/PR. With a median follow-up of 4.8 years, 3-year progression-free(PFS) and overall survival were 48.6% (95%-CI:39.5–57%) and 55.6% (95%-CI:46.5–63.8%). Non-relapse mortality at 1 year was 14.8% (95%-CI:9.3–21.5%) and 1-year relapse incidence 29.6% (95%-CI:21.9–37.6%). In multivariate analyses, shorter time interval (0–12 months) between diagnosis and allo-HSCT [HR = 2.12 (95%-CI:1.03–4.34); P = 0.04] and transplantation not in CR/PR [HR = 2.20 (95%-CI:0.98–4.95); P = 0.056] reduced PFS. Programmed cell death protein 1(PD-1/PD-L1) treatment before HSCT neither increased GVHD nor impacted survival. We demonstrate that allo-HSCT can achieve long-term survival in approximately half of pts allografted for NKTCL.
- Published
- 2023
43. Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09–09): a randomised, open-label, multicentre, phase 3 trial
- Author
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Hartmut Döhner, Daniela Weber, Julia Krzykalla, Walter Fiedler, Michael W M Kühn, Thomas Schroeder, Karin Mayer, Michael Lübbert, Mohammed Wattad, Katharina Götze, Lars Fransecky, Elisabeth Koller, Gerald Wulf, Jan Schleicher, Mark Ringhoffer, Richard Greil, Bernd Hertenstein, Jürgen Krauter, Uwe M Martens, David Nachbaur, Maisun Abu Samra, Sigrid Machherndl-Spandl, Nadezda Basara, Claudia Leis, Anika Schrade, Silke Kapp-Schwoerer, Sibylle Cocciardi, Lars Bullinger, Felicitas Thol, Michael Heuser, Peter Paschka, Verena I Gaidzik, Maral Saadati, Axel Benner, Richard F Schlenk, Konstanze Döhner, Arnold Ganser, Michael W.M. Kühn, Mohammad Wattad, Uwe M. Martens, Verena I. Gaidzik, and Richard F. Schlenk
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Hematology - Published
- 2023
44. KIR2DS4 and Its Variant KIR1D in KIR-AA Genotype Donors Showed Differential Survival Impact in Patients with Lymphoid Disease after HLA-Matched Unrelated Hematopoietic Stem Cell Transplantation
- Author
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Sowmya Gowdavally, Chrysanthi Tsamadou, Uwe Platzbecker, Elisa Sala, Thomas Valerius, Stefan Klein, Nicolaus Kröger, Gerald Wulf, Hermann Einsele, Lorenz Thurner, Kerstin Schaefer-Eckart, Sebastian Freitag, Jochen Casper, Mareike Dürholt, Martin Kaufmann, Bernd Hertenstein, Mark Ringhoffer, Sandra Schmeller, Christine Neuchel, Immanuel Rode, Elisa Maria Amann, Anita Richter, Hubert Schrezenmeier, Joannis Mytilineos, and Daniel Fuerst
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
45. Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation
- Author
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Alexandros Spyridonidis, Myriam Labopin, Tobias Gedde-Dahl, Arnold Ganser, Matthias Stelljes, Charles Craddock, Eva Maria Wagner, Jurjen Versluis, Thomas Schroeder, Igor Wolfgang Blau, Gerald Wulf, Peter Dreger, Gitte Olesen, Henrik Sengeloev, Nicolaus Kröger, Victoria Potter, Edouard Forcade, Jakob Passweg, Régis Peffault de Latour, Johan Maertens, Keith Wilson, Jean-Henri Bourhis, Bipin Savani, Fabio Ciceri, Arnon Nagler, and Mohamad Mohty
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
46. Organ Complications after CD19 CAR T-Cell Therapy for Large B Cell Lymphoma. a Retrospective Study from the EBMT Transplant Complications and Lymphoma Working Partys
- Author
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Olaf Penack, Christophe Peczynski, Christian Koenecke, Emmanuelle Polge, Victoria Potter, Ibrahim Yakoub-Agha, Nathalie Fegueux, Michael Daskalakis, Matthew P. Collin, Peter Dreger, Nicolaus Kröger, Urs Schanz, Adrian Bloor, Arnold Ganser, Caroline Besley, Gerald Wulf, Urban Novak, Ivan Moiseev, Helene Schoemans, Grzegorz W Basak, Christian Chabannon, Anna Sureda, Bertram Glass, and Zinaida Peric
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
47. CART Therapy or Allogeneic Stem Cell Transplantation in ≥ Third Line Treatment of Large B Cell Lymphoma (LBCL)
- Author
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Bertram Glass, Anna Sureda, Ariane Boumendil, Peter Dreger, Paolo Corradini, Ron Ram, Nicolaus Kroeger, Luca Castagna, Thomas Pabst, Mi Kwon, Gerald Wulf, Alejandro Martín García-Sancho, Carlos Solano, Matthias Stelljes, Hans Christian Reinhardt, Marie Thérèse Rubio, Ram Malladi, Didier Blaise, Caroline Besley, Edouard Forcade, Malte von Bonin, Jürgen Finke, Inken Hilgendorf, Joaquín Martínez-López, Jose A. Perez-Simon, Wolfgang Bethge, and Norbert Schmitz
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
48. Outcomes of second allogeneic stem cell transplantation and anti‐relapse strategies in patients with relapsed/refractory acute myeloid leukemia: A unicentric retrospective analysis
- Author
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Evgenii Shumilov, Justin Hasenkamp, Markus Maulhardt, Paolo Mazzeo, Nicole Schmidt, Hristo Boyadzhiev, Wolfram Jung, Christina Ganster, Detlef Haase, Raphael Koch, and Gerald Wulf
- Subjects
Leukemia, Myeloid, Acute ,Sulfonamides ,Cancer Research ,Oncology ,Recurrence ,Azacitidine ,Hematopoietic Stem Cell Transplantation ,Humans ,Hematology ,General Medicine ,Bridged Bicyclo Compounds, Heterocyclic ,Retrospective Studies - Abstract
Second allogeneic stem cell transplantation (allo-SCT2) represents a rescue option for selected patients (pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML). Still, relapse rates post-allo-SCT2 remain high and effective anti-relapse strategies and predictive biomarkers remain to be defined. We here analyzed a cohort of 41 AML patients (pts) undergoing allo-SCT2 in our center. Allo-SCT2 induced a third hematologic complete remission (CR) in 37 pts, at costs of a 36% non-relapse mortality rate. Furthermore, 19 pts eventually relapsed post allo-SCT2. Addressing relapse after allo-SCT2, 14 pts (74%) underwent cell-based anti-relapse strategies, including third allogeneic transplantation (allo-SCT3; 3/14), donor lymphocyte infusions (DLIs) combined with either 5-azacytidin and venetoclax (4/14) or chemotherapeutic agents (7/14). Notably, six of seven pts (86%) who received either allo-SCT3 or a combination therapy of DLIs, 5-azacytidine and venetoclax achieved CR despite poor cytogenetics post-allo-SCT2 (e.g., TP53). Finally, 11 of 41 pts were alive at the last follow-up (seven CR2, three CR3, one partial remission) resulting in estimated 2- and 5-year overall survival of 35% and 25%, respectively.
- Published
- 2022
49. Supplementary Tables S1-S11 from Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
- Author
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Anna Sureda, Olalekan O. Oluwole, Christina To, Paul Cheng, Julia T. Snider, Jina Shah, Simone Filosto, Saran Vardhanabhuti, Linqiu Du, Aaron P. Rapoport, Patrick Johnston, Gerald Wulf, John M. Pagel, Caron A. Jacobson, Marie José Kersten, Lori Leslie, Luciano Wannesson, Umar Farooq, Miguel-Angel Perales, Matthew L. Ulrickson, David B. Miklos, Tom van Meerten, Mahmoud Elsawy, Armin Ghobadi, Michael Dickinson, Frederick L. Locke, and Jason R. Westin
- Abstract
Tabulated data supporting ZUMA-7 elderly analysis Supplementary Table S1. Patient-reported outcomes instruments Supplementary Table S2. Axi-cel delivery and administration time Supplementary Table S3. Summary of efficacy and safety outcomes in patients ≥65 years versus all patients in ZUMA-7 Supplementary Table S4. Serious adverse events in at least 3 patients in patients ≥65 years Supplementary Table S5. Summary of cytopenias present on or after 90 days from initiation of definitive therapy on protocol in patients ≥65 years Supplementary Table S6. Deaths in axi-cel and SOC arms for patients ≥65 years (safety analysis set) Supplementary Table S7. Summary of serum analytes in patients
- Published
- 2023
50. Data from Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
- Author
-
Anna Sureda, Olalekan O. Oluwole, Christina To, Paul Cheng, Julia T. Snider, Jina Shah, Simone Filosto, Saran Vardhanabhuti, Linqiu Du, Aaron P. Rapoport, Patrick Johnston, Gerald Wulf, John M. Pagel, Caron A. Jacobson, Marie José Kersten, Lori Leslie, Luciano Wannesson, Umar Farooq, Miguel-Angel Perales, Matthew L. Ulrickson, David B. Miklos, Tom van Meerten, Mahmoud Elsawy, Armin Ghobadi, Michael Dickinson, Frederick L. Locke, and Jason R. Westin
- Abstract
Purpose:Older patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) may be considered ineligible for curative-intent therapy including high-dose chemotherapy with autologous stem-cell transplantation (HDT-ASCT). Here, we report outcomes of a preplanned subgroup analysis of patients ≥65 years in ZUMA-7.Patients and Methods:Patients with LBCL refractory to or relapsed ≤12 months after first-line chemoimmunotherapy were randomized 1:1 to axicabtagene ciloleucel [axi-cel; autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy] or standard of care (SOC; 2–3 cycles of chemoimmunotherapy followed by HDT-ASCT). The primary endpoint was event-free survival (EFS). Secondary endpoints included safety and patient-reported outcomes (PROs).Results:Fifty-one and 58 patients aged ≥65 years were randomized to axi-cel and SOC, respectively. Median EFS was greater with axi-cel versus SOC (21.5 vs. 2.5 months; median follow-up: 24.3 months; HR, 0.276; descriptive P < 0.0001). Objective response rate was higher with axi-cel versus SOC (88% vs. 52%; OR, 8.81; descriptive P < 0.0001; complete response rate: 75% vs. 33%). Grade ≥3 adverse events occurred in 94% of axi-cel and 82% of SOC patients. No grade 5 cytokine release syndrome or neurologic events occurred. In the quality-of-life analysis, the mean change in PRO scores from baseline at days 100 and 150 favored axi-cel for EORTC QLQ-C30 Global Health, Physical Functioning, and EQ-5D-5L visual analog scale (descriptive P < 0.05). CAR T-cell expansion and baseline serum inflammatory profile were comparable in patients ≥65 and Conclusions:Axi-cel is an effective second-line curative-intent therapy with a manageable safety profile and improved PROs for patients ≥65 years with R/R LBCL.
- Published
- 2023
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