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2. Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial

Author

Alakel, Nael, Albring, Jörn, Berdel, Wolfgang E., Bethge, Wolfgang, Bornhäuser, Martin, Bug, Gesine, Buhl, Christoph, Call, Simon, Crysandt, Martina, Egger-Heidrich, Katharina, Eßeling, Eva, Faul, Christoph, Franke, Georg-Nikolaus, Georgi, Julia-Annabell, Glück-Wolf, Julia, Groth, Christoph, Hauptrock, Beate, Heidenreich, Daniela, Janjetovic, Snjezana, Jost, Edgar, Kaufmann, Martin, Kindler, Thomas, Klein, Stefan A., Krause, Stefan W., Kreil, Sebastian, Kretschmann, Theresa, Kunadt, Desiree, Lang, Fabian, Lenz, Georg, Martin, Sonja, Marx, Julia, Middeke, Jan-Moritz, Mikesch, Jan-Henrik, Müller, Lutz P., Müller, Nadine, Niederland, Judith, Parmentier, Stefani, Petzold, Kathrin, Platzbecker, Uwe, Rank, Andreas, Reicherts, Christian, Röllig, Christoph, Rösler, Wolf, Schäfer-Eckart, Kerstin, Schaffrath, Judith, Schaich, Markus, Schetelig, Johannes, Schliemann, Christoph, Schmid, Christoph, Schneidawind, Dominik, Schubert, Jörg, Serve, Hubert, Sockel, Katja, Steffen, Björn, Stelljes, Matthias, Teipel, Raphael, von Bonin, Malte, Wagner-Drouet, Eva, Wass, Maxi, Wendelin, Knut, Middeke, Jan Moritz, Wagner-Drouet, Eva-Maria, Müller, Lutz P, Krause, Stefan W, Klein, Stefan A, Baldauf, Henning, Stölzel, Friedrich, Petzold, Cathleen, Kriege, Oliver, Berdel, Wolfgang E, Ehninger, Gerhard, and Schmidt, Alexander H

Published
2024
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3. Patient-tailored adoptive immunotherapy with EBV-specific T cells from related and unrelated donors

Author

Bonifacius, Agnes, Lamottke, Britta, Tischer-Zimmermann, Sabine, Schultze- Florey, Rebecca, Goudeva, Lilia, Heuft, Hans-Gert, Arseniev, Lubomir, Beier, Rita, Beutel, Gernot, Cario, Gunnar, Frohlich, Birgit, Greil, Johann, Hansmann, Leo, Hasenkamp, Justin, Hofs, Michaela, Hundsdoerfer, Patrick, Jost, Edgar, Kafa, Kinan, Kriege, Oliver, Kroger, Nicolaus, Mathas, Stephan, Meisel, Roland, Nathrath, Michaela, Putkonen, Mervi, Ravens, Sarina, Reinhardt, Hans Christian, Sala, Elisa, Sauer, Martin G., Schmitt, Clemens, Schroers, Roland, Steckel, Nina Kristin, Trappe, Ralf Ulrich, Verbeek, Mareike, Wolff, Daniel, Blasczyk, Rainer, Eiz-Vesper, Britta, and Maecker-Kolhoff, Britta

Subjects
Cells -- Transplantation, Epstein-Barr virus diseases -- Complications and side effects, T cells -- Health aspects, Immunotherapy -- Methods, Lymphoproliferative disorders -- Care and treatment, Graft versus host reaction -- Care and treatment, Health care industry
Abstract

BACKGROUND. Adoptive transfer of EBV-specific T cells can restore specific immunity in immunocompromised patients with EBV-associated complications. METHODS. We provide results of a personalized T cell manufacturing program evaluating donor, patient, T cell product, and outcome data. Patient-tailored clinical-grade EBV-specific cytotoxic T lymphocyte (EBV-CTL) products from stem cell donors (SCDs), related third-party donors (TPDs), or unrelated TPDs from the allogeneic T cell donor registry (alloCELL) at Hannover Medical School were manufactured by immunomagnetic selection using a CliniMACS Plus or Prodigy device and the EBV PepTivators EBNA-1 and Select. Consecutive manufacturing processes were evaluated, and patient outcome and side effects were retrieved by retrospective chart analysis. RESULTS. Forty clinical-grade EBV-CTL products from SCDs, related TPDs, or unrelated TPDs were generated for 37 patients with refractory EBV infections or EBV-associated malignancies with and without a history of transplantation, within 5 days (median) after donor identification. Thirty-four patients received 1-14 EBV-CTL products (fresh and cryopreserved). EBV-CTL transfer led to a complete response in 20 of 29 patients who were evaluated for clinical response. No infusion-related toxicity was reported. EBV-specific T cells in patients' blood were detectable in 16 of 18 monitored patients (89%) after transfer, and their presence correlated with clinical response. CONCLUSION. Personalized clinical-grade manufacture of EBV-CTL products via immunomagnetic selection from SCDs, related TPDs, or unrelated TPDs in a timely manner is feasible. Overall, EBV-CTLs were clinically effective and well tolerated. Our data suggest EBV-CTL transfer as a promising therapeutic approach for immunocompromised patients with refractory EBV-associated diseases beyond HSCT, as well as patients with preexisting organ dysfunction. TRIAL REGISTRATION. Not applicable. FUNDING. This study was funded in part by the German Research Foundation (DFG, 158989968/SFB 900), the Deutsche Kinderkrebsstiftung (DKS 2013.09), Wilhelm-Sander-Stiftung (reference 2015.097.1), Ellen-Schmidt-Program of Hannover Medical School, and German Federal Ministry of Education and Research (reference 01E00802)., Introduction Morbidity and mortality in patients with hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) are frequently caused by graft rejection or graft-versus-host disease (GvHD) and increased by [...]

Published
2023
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5. Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia

Author

Rautenberg, Christina, Stölzel, Friedrich, Röllig, Christoph, Stelljes, Matthias, Gaidzik, Verena, Lauseker, Michael, Kriege, Oliver, Verbeek, Mareike, Unglaub, Julia Marie, Thol, Felicitas, Krause, Stefan W., Hänel, Mathias, Neuerburg, Charlotte, Vucinic, Vladan, Jehn, Christian-Friedrich, Severmann, Julia, Wass, Maxi, Fransecky, Lars, Chemnitz, Jens, Holtick, Udo, Schäfer-Eckart, Kerstin, Schröder, Josephine, Kraus, Sabrina, Krüger, William, Kaiser, Ulrich, Scholl, Sebastian, Koch, Kathrin, Henning, Lea, Kobbe, Guido, Haas, Rainer, Alakel, Nael, Röhnert, Maximilian-Alexander, Sockel, Katja, Hanoun, Maher, Platzbecker, Uwe, Holderried, Tobias A. W., Morgner, Anke, Heuser, Michael, Sauer, Tim, Götze, Katharina S., Wagner-Drouet, Eva, Döhner, Konstanze, Döhner, Hartmut, Schliemann, Christoph, Schetelig, Johannes, Bornhäuser, Martin, Germing, Ulrich, Schroeder, Thomas, and Middeke, Jan Moritz

Published
2021
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6. Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial

Author

Stelljes, Matthias, Middeke, Jan Moritz, Bug, Gesine, Wagner-Drouet, Eva-Maria, Müller, Lutz P, Schmid, Christoph, Krause, Stefan W, Bethge, Wolfgang, Jost, Edgar, Platzbecker, Uwe, Klein, Stefan A, Schubert, Jörg, Niederland, Judith, Kaufmann, Martin, Schäfer-Eckart, Kerstin, Schaich, Markus, Baldauf, Henning, Stölzel, Friedrich, Petzold, Cathleen, Röllig, Christoph, Alakel, Nael, Steffen, Björn, Hauptrock, Beate, Schliemann, Christoph, Sockel, Katja, Lang, Fabian, Kriege, Oliver, Schaffrath, Judith, Reicherts, Christian, Berdel, Wolfgang E, Serve, Hubert, Ehninger, Gerhard, Schmidt, Alexander H, Bornhäuser, Martin, Mikesch, Jan-Henrik, Schetelig, Johannes, Alakel, Nael, Albring, Jörn, Berdel, Wolfgang E., Bethge, Wolfgang, Bornhäuser, Martin, Bug, Gesine, Buhl, Christoph, Call, Simon, Crysandt, Martina, Egger-Heidrich, Katharina, Eßeling, Eva, Faul, Christoph, Franke, Georg-Nikolaus, Georgi, Julia-Annabell, Glück-Wolf, Julia, Groth, Christoph, Hauptrock, Beate, Heidenreich, Daniela, Janjetovic, Snjezana, Jost, Edgar, Kaufmann, Martin, Kindler, Thomas, Klein, Stefan A., Krause, Stefan W., Kreil, Sebastian, Kretschmann, Theresa, Kunadt, Desiree, Lang, Fabian, Lenz, Georg, Martin, Sonja, Marx, Julia, Middeke, Jan-Moritz, Mikesch, Jan-Henrik, Müller, Lutz P., Müller, Nadine, Niederland, Judith, Parmentier, Stefani, Petzold, Kathrin, Platzbecker, Uwe, Rank, Andreas, Reicherts, Christian, Röllig, Christoph, Rösler, Wolf, Schäfer-Eckart, Kerstin, Schaffrath, Judith, Schaich, Markus, Schetelig, Johannes, Schliemann, Christoph, Schmid, Christoph, Schneidawind, Dominik, Schubert, Jörg, Serve, Hubert, Sockel, Katja, Steffen, Björn, Stelljes, Matthias, Teipel, Raphael, von Bonin, Malte, Wagner-Drouet, Eva, Wass, Maxi, and Wendelin, Knut

Abstract

Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear.

Published
2024
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7. Management of Patients Undergoing CAR-T Cell Therapy in Germany.

Author

Penack, Olaf, Dreger, Peter, Ajib, Salem, Ayuk, Francis, Baermann, Ben-Niklas, Bug, Gesine, Kriege, Oliver, Jentzsch, Madlen, Kobbe, Guido, Koenecke, Christian, Lutz, Mathias, Martin, Sonja, Schlegel, Paul-Gerhard, Schroers, Roland, von Tresckow, Bastian, Vucinic, Vladan, Subklewe, Marion, Bethge, Wolfgang, and Wolff, Daniel

Subjects
STEM cell transplantation, CELLULAR therapy, HEMATOPOIETIC stem cell transplantation, CELL transplantation, CYTOKINE release syndrome, NON-Hodgkin's lymphoma
Abstract

Introduction: Chimeric antigen receptor positive T cell (CAR-T cell) treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-Hodgkin's lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in the prevention, diagnosis, and management of short- and long-term complications. Methods: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research, the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. Results: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no – or low quality – clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, IgG substitution, autologous stem cell backups, anti-infective prophylaxis, and vaccinations. Conclusion: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome. [ABSTRACT FROM AUTHOR]

Published
2024
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8. One fits all: a highly sensitive combined ddPCR/pyrosequencing system for the quantification of microchimerism after hematopoietic and solid organ transplantation

Author

Häuser, Friederike, primary, Mittler, Jens, additional, Hantal, Misra Simge, additional, Greulich, Lilli, additional, Hermanns, Martina, additional, Shrestha, Annette, additional, Kriege, Oliver, additional, Falter, Tanja, additional, Immel, Uta D., additional, Herold, Stephanie, additional, Schuch, Brigitte, additional, Lackner, Karl J., additional, Rossmann, Heidi, additional, and Radsak, Markus, additional

Published
2023
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10. Real-World Experience of CPX-351 As First-Line Treatment in 188 Patients with Acute Myeloid Leukemia

Author

Rautenberg, Christina, primary, Stölzel, Friedrich, additional, Röllig, Christoph, additional, Stelljes, Matthias, additional, Gaidzik, Verena I, additional, Lauseker, Michael, additional, Kriege, Oliver, additional, Verbeek, Mareike, additional, Unglaub, Julia M., additional, Thol, Felicitas, additional, Krause, Stefan W., additional, Haenel, Mathias, additional, Neuerburg, Charlotte, additional, Vucinic, Vladan, additional, Jehn, Christian, additional, Severmann, Julia, additional, Wass, Maxi, additional, Fransecky, Lars, additional, Chemnitz, Jens, additional, Holtick, Udo, additional, Schäfer-Eckart, Kerstin, additional, Schröder, Josephine, additional, Kraus, Sabrina, additional, Krüger, William Hermann, additional, Kaiser, Ulrich, additional, Scholl, Sebastian, additional, Henning, Lea, additional, Kobbe, Guido, additional, Haas, Rainer, additional, Alakel, Nael, additional, Röhnert, Maximilian Alexander, additional, Sockel, Katja, additional, Hanoun, Maher, additional, Platzbecker, Uwe, additional, Holderried, Tobias A. W., additional, Morgner, Anke, additional, Heuser, Michael, additional, Sauer, Tim, additional, Goetze, Katharina S., additional, Wagner, Eva Maria, additional, Döhner, Konstanze, additional, Döhner, Hartmut, additional, Schliemann, Christoph, additional, Schetelig, Johannes, additional, Bornhäuser, Martin, additional, Germing, Ulrich, additional, Schroeder, Thomas, additional, and Middeke, Moritz Moritz, additional

Published
2021
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11. Correction to: Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents—a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group

Author

Schuler, Esther, Wagner-Drouet, Eva-Maria, Ajib, Salem, Bug, Gesine, Crysandt, Martina, Dressler, Sabine, Hausmann, Andreas, Heidenreich, Daniela, Hirschbühl, Klaus, Hoepting, Matthias, Jost, Edgar, Kaivers, Jennifer, Klein, Stefan, Koldehoff, Michael, Kordelas, Lambros, Kriege, Oliver, Müller, Lutz P., Rautenberg, Christina, Schaffrath, Judith, Schmid, Christoph, Wolff, Daniel, Haas, Rainer, Bornhäuser, Martin, Schroeder, Thomas, and Kobbe, Guido

Subjects
Salvage Therapy, Sulfonamides, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation, Correction, Kaplan-Meier Estimate, DNA Methylation, Allografts, Bridged Bicyclo Compounds, Heterocyclic, Decitabine, Combined Modality Therapy, Thrombocytopenia, Leukemia, Myeloid, Acute, Leukocyte Count, Recurrence, Germany, Myelodysplastic Syndromes, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Drug Evaluation, Humans, Tumor Lysis Syndrome, Immunosuppressive Agents, Febrile Neutropenia, Retrospective Studies
Abstract

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRD

Published
2021

12. Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents : A retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group

Author

Schuler, Esther, Wagner-Drouet, Eva-Maria, Jost, Edgar, Kaivers, Jennifer, Klein, Stefan, Koldehoff, Michael, Kordelas, Lambros, Kriege, Oliver, Müller, Lutz P., Rautenberg, Christina, Schaffrath, Judith, Schmid, Christoph, Ajib, Salem, Wolff, Daniel, Haas, Rainer, Bornhäuser, Martin, Schroeder, Thomas, Kobbe, Guido, German Cooperative Transplant Study Group, Bug, Gesine, Crysandt, Martina, Dressler, Sabine, Hausmann, Andreas, Heidenreich, Daniela, Hirschbühl, Klaus, and Hoepting, Matthias

Subjects
Oncology, medicine.medical_specialty, Myeloid, medicine.medical_treatment, Azacitidine, Medizin, Decitabine, Salvage therapy, Hypomethylating agents, Hematopoietic stem cell transplantation, Neutropenia, Venetoclax, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Medicine, ddc:610, Relapse, Hematology, business.industry, General Medicine, medicine.disease, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Allogeneic hematopoietic stem cell transplantation, Original Article, DLI, business, 030215 immunology, medicine.drug
Abstract

Annals of hematology 100(4), 959-968 (2021). doi:10.1007/s00277-020-04321-x, Published by Springer, Berlin ; Heidelberg ; New York

Published
2021

13. Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia

Author

Rautenberg, Christina, Stölzel, Friedrich, Röllig, Christoph, Stelljes, Matthias, Gaidzik, Verena, Lauseker, Michael, Kriege, Oliver, Verbeek, Mareike, Unglaub, Julia Marie, Thol, Felicitas, Krause, Stefan W., Hänel, Mathias, Neuerburg, Charlotte, Vucinic, Vladan, Jehn, Christian-Friedrich, Severmann, Julia, Wass, Maxi, Fransecky, Lars, Chemnitz, Jens, Holtick, Udo, Schäfer-Eckart, Kerstin, Schröder, Josephine, Kraus, Sabrina, Krüger, William, Kaiser, Ulrich, Scholl, Sebastian, Koch, Kathrin, Henning, Lea, Kobbe, Guido, Haas, Rainer, Alakel, Nael, Röhnert, Maximilian-Alexander, Sockel, Katja, Hanoun, Maher, Platzbecker, Uwe, Holderried, Tobias A. W., Morgner, Anke, Heuser, Michael, Sauer, Tim, Götze, Katharina S., Wagner-Drouet, Eva, Döhner, Konstanze, Döhner, Hartmut, Schliemann, Christoph, Schetelig, Johannes, Bornhäuser, Martin, Germing, Ulrich, Schroeder, Thomas, and Middeke, Jan Moritz

Subjects
Article, Haematological cancer, Leukaemia, ddc
Published
2020

14. Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation with Venetoclax, Hypomethylating Agents and DLI - a Retrospective Multi Center Study

Author

Schuler, Esther, primary, Wagner-Drouet, Eva-Maria, additional, Ajib, Salem, additional, Bug, Gesine, additional, Crysandt, Martina, additional, Dressler, Sabine, additional, Hausmann, Andreas, additional, Heidenreich, Daniela, additional, Hirschbühl, Klaus, additional, Hoepting, Matthias, additional, Jost, Edgar, additional, Kaivers, Jennifer, additional, Klein, Stefan A, additional, Kordelas, Lambros, additional, Kriege, Oliver, additional, Mueller, Lutz Peter, additional, Rautenberg, Christina, additional, Schaffrath, Judith, additional, Schmid, Christoph, additional, Wolff, Daniel, additional, Bornhaeuser, Martin, additional, Schroeder, Thomas, additional, and Kobbe, Guido, additional

Published
2019
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16. The Bruton tyrosine kinase inhibitor ibrutinib abrogates triggering receptor on myeloid cells 1-mediated neutrophil activation

Author

Stadler, Nicole, primary, Hasibeder, Astrid, additional, Lopez, Pamela Aranda, additional, Teschner, Daniel, additional, Desuki, Alexander, additional, Kriege, Oliver, additional, Weber, Alexander N. R., additional, Schulz, Christoph, additional, Michel, Christian, additional, Heβ, Georg, additional, and Radsak, Markus P., additional

Published
2017
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17. Idelalisib Impairs TREM-1 and TLR Mediated Neutrophil Activation

Author

Hasibeder, Astrid, primary, Stadler, Nicole, additional, Aranda Lopez, Pamela, additional, Desuki, Alexander, additional, Kriege, Oliver, additional, Weber, Alexander N.R., additional, Michel, Christian, additional, Teschner, Daniel, additional, Hess, Georg, additional, Theobald, Matthias, additional, and Radsak, Markus, additional

Published
2016
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18. Ibrutinib Abrogates TREM-1 Mediated Neutrophil Activation

Author

Stadler, Nicole, primary, Hasibeder, Astrid, additional, Aranda Lopez, Pamela, additional, Desuki, Alexander, additional, Kriege, Oliver, additional, Weber, Alexander N.R., additional, Michel, Christian, additional, Teschner, Daniel, additional, Hess, Georg, additional, Theobald, Matthias, additional, and Radsak, Markus, additional

Published
2016
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19. Implementation of CMV-T-Track® in Clinical Routine to Guide Management of CMV Reactivation

Author

Wißkirchen, Jonas, Wolff, Diana, Ries, Isabelle, Kriege, Oliver, Wölfinger, Pascal, Hauptrock, Beate, Theobald, Matthias, and Wagner Drouet, Eva-Maria

Abstract

Background: Despite Letermovir prophylaxis, reactivation of cytomegalovirus (CMV), requiring close monitoring and preemptive antiviral treatment, remains to be an issue after allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring CMV-specific cellular immunity can help to identify patients at risk and may guide monitoring intervals and therapeutic decisions.

Published
2023
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20. Targeting Aberrant Ncam (neural cell adhesion molecule; CD56) Expression in Acute Myeloid Leukemia

Author

Sasca, Daniel, primary, Schueler, Andrea, additional, Szybinski, Jakub, additional, Kriege, Oliver, additional, Kunz, Kerstin, additional, Fehr, Eva Marie, additional, Haehnel, Patricia, additional, Gebhardt, Wolf Henning, additional, Reid, Gerge, additional, Theobald, Matthias, additional, Bullinger, Lars, additional, and Kindler, Thomas, additional

Published
2015
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21. NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML

Author

Sasca, Daniel, Szybinski, Jakub, Schüler, Andrea, Shah, Viral, Heidelberger, Jan, Haehnel, Patricia S., Dolnik, Anna, Kriege, Oliver, Fehr, Eva-Marie, Gebhardt, Wolf H., Reid, George, Scholl, Claudia, Theobald, Matthias, Bullinger, Lars, Beli, Petra, and Kindler, Thomas

Abstract

Neural cell adhesion molecule 1 (NCAM1; CD56) is expressed in up to 20% of acute myeloid leukemia (AML) patients. NCAM1 is widely used as a marker of minimal residual disease; however, the biological function of NCAM1 in AML remains elusive. In this study, we investigated the impact of NCAM1 expression on leukemogenesis, drug resistance, and its role as a biomarker to guide therapy. Beside t(8;21) leukemia, NCAM1 expression was found in most molecular AML subgroups at highly heterogeneous expression levels. Using complementary genetic strategies, we demonstrated an essential role of NCAM1 in the regulation of cell survival and stress resistance. Perturbation of NCAM1 induced cell death or differentiation and sensitized leukemic blasts toward genotoxic agents in vitro and in vivo. Furthermore, Ncam1 was highly expressed in leukemic progenitor cells in a murine leukemia model, and genetic depletion of Ncam1 prolonged disease latency and significantly reduced leukemia-initiating cells upon serial transplantation. To further analyze the mechanism of the NCAM1-associated phenotype, we performed phosphoproteomics and transcriptomics in different AML cell lines. NCAM1 expression strongly associated with constitutive activation of the MAPK-signaling pathway, regulation of apoptosis, or glycolysis. Pharmacological inhibition of MEK1/2 specifically inhibited proliferation and sensitized NCAM1+ AML cells to chemotherapy. In summary, our data demonstrate that aberrant expression of NCAM1 is involved in the maintenance of leukemic stem cells and confers stress resistance, likely due to activation of the MAPK pathway. Targeting MEK1/2 sensitizes AML blasts to genotoxic agents, indicating a role for NCAM1 as a biomarker to guide AML treatment.

Published
2019
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23. Correction to: Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Author

Schuler E, Wagner-Drouet EM, Ajib S, Bug G, Crysandt M, Dressler S, Hausmann A, Heidenreich D, Hirschbühl K, Hoepting M, Jost E, Kaivers J, Klein S, Koldehoff M, Kordelas L, Kriege O, Müller LP, Rautenberg C, Schaffrath J, Schmid C, Wolff D, Haas R, Bornhäuser M, Schroeder T, and Kobbe G

Published
2021
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24. Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Author

Schuler E, Wagner-Drouet EM, Ajib S, Bug G, Crysandt M, Dressler S, Hausmann A, Heidenreich D, Hirschbühl K, Hoepting M, Jost E, Kaivers J, Klein S, Koldehoff M, Kordelas L, Kriege O, Müller LP, Rautenberg C, Schaffrath J, Schmid C, Wolff D, Haas R, Bornhäuser M, Schroeder T, and Kobbe G

Subjects
Allografts, Antineoplastic Combined Chemotherapy Protocols adverse effects, Azacitidine administration & dosage, Azacitidine adverse effects, Azacitidine pharmacology, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Combined Modality Therapy, DNA Methylation drug effects, Decitabine administration & dosage, Decitabine adverse effects, Decitabine pharmacology, Drug Evaluation, Febrile Neutropenia blood, Febrile Neutropenia chemically induced, Germany epidemiology, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute therapy, Leukocyte Count, Myelodysplastic Syndromes therapy, Recurrence, Retrospective Studies, Sulfonamides administration & dosage, Sulfonamides adverse effects, Thrombocytopenia blood, Thrombocytopenia chemically induced, Transplantation Conditioning, Tumor Lysis Syndrome etiology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy, Salvage Therapy adverse effects
Abstract

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRD neg , 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.

Published
2021
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