125 results on '"U. Holtick"'
Search Results
2. S235: A TWO-PART, SINGLE- AND TWO-ARM RANDOMIZED, OPEN-LABEL STUDY TO EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF THE S1P RECEPTOR MODULATOR KRP203 IN SUBJECTS WITH HEMATOLOGICAL MALIGNANCIES
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S. dertschnig, J. finke, D. heim, U. schanz, E. holler, U. holtick, G. socié, T. teshima, C. bucher, and J. passweg
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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3. P1184: PHASE I TRIAL OF MB-CART2019.1 IN PATIENTES WITH RELAPSED OR REFRATORY B-CELL NON-HODGKIN LYMPHOMA: 2 YEAR FOLLOW-UP REPORT
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P. Borchmann, A. Lohneis, P. Gödel, H. Balke-Want, C. Schmid, F. Ayuk, S. Holtkamp, L. Hanssens, G. Zadoyan, B. Friedrichs, M. Assenmacher, I. Bürger, D. Schneider, T. Overstijns, C. Scheid, U. Holtick, S. Miltenyi, and M. Hallek
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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4. P1447: INFERIOR OUTCOMES OF EU VS. US PATIENTS WITH RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA AFTER CD19 CAR T-CELL THERAPY ARE IMPACTED BY BASELINE RISK FACTORS AND CAR PRODUCT CHOICE
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V. Bücklein, A. Perez, G. Iacoboni, K. Rejeski, U. Holtick, O. Penack, S. Kharboutli, V. Blumenberg, J. Ackermann, L. Frölich, G. Johnson, K. Patel, B. Arciola, C. Schmidt, O. Albanyan, P. Gödel, E. Hoster, L. Bullinger, A. Mackensen, F. Locke, M. von Bergwelt, P. Barba, M. D. Jain, and M. Subklewe
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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5. P1448: LONG-TERM SURVIVORS AFTER FAILURE OF CAR-T CELL THERAPY FOR R/R LARGE B-CELL LYMPHOMA (LBCL): A GLA/DRST STUDY
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P. Derigs, W. Bethge, U. Holtick, B. von Tresckow, F. Ayuk, O. Penack, V. Vucinic, M. von Bonin, C. Baldus, D. Mougiakakos, G. Wulf, U. Schnetzke, M. Stelljes, S. Thomas, R. Schroers, N. Kroeger, and P. Dreger
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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6. 191P Preliminary biomarker and safety results of SQZ-PBMC-HPV at RP2D in monotherapy and combination with checkpoint inhibitors in HLA A*02+ patients with recurrent, locally advanced, or metastatic HPV16+ solid tumors
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A. Jimeno, N.R. Miselis, J.C. Park, J. Jennings, N. Dhani, U. Holtick, W.T. Iams, K. Rodabaugh, N. Nair, M. Kornacker, S.M. Loughhead, H. Bernstein, R. Zwirtes, R.R. Ji, M. Warren, and A. Sharei
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Oncology ,Immunology and Allergy - Published
- 2022
7. Allogene Blutstammzelltransplantation – ein Überblick
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Christoph Scheid, U. Holtick, Michael Hallek, and J. M. Chemnitz
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Transplantation ,Gynecology ,Ophthalmology ,Haematopoiesis ,medicine.medical_specialty ,Chronic disease ,Graft-versus-host disease ,business.industry ,Medicine ,Stem cell ,business ,medicine.disease - Abstract
Die allogene Blutstammzell- oder Knochenmarktransplantation ist eine effektive kurative Therapieoption fur chemotherapierefraktare oder rezidivierte hamatologische Neoplasien wie Leukamien und Lymphome. Nach einer Vorbehandlung mittels Chemotherapie mit oder ohne Ganzkorperbestrahlung werden Spenderzellen zur Rekonstitution der Hamatopoese verabreicht. Diese Spenderzellen uben einen uber den Effekt von Chemotherapie hinausgehenden Immuneffekt zur Kontrolle oder Eradikation der Grunderkrankung aus. Einhergehend mit diesem sog. Transplantat-versus-Tumor-Effekt (graft-versus-tumor effect, GvT) tritt haufig eine akute und/oder chronische Transplantat-gegen-Wirt-Erkrankung auf (graft-versus-host disease, GvHD), die substanziell die Mortalitat und Morbiditat nach Transplantation mitbestimmt. Die Balance zwischen GvHD und GvT mittels verschiedener Parameter wie Spenderauswahl, Stammzellquelle, Konditionierung, Immunerholung und Immunsuppression stellt die Herausforderung fur die allogene Stammzelltransplantation dar.
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- 2015
8. [Allogeneic haematopoietic stem cell transplantation - an overview]
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U, Holtick, J M, Chemnitz, M, Hallek, and C, Scheid
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Leukemia ,Transplantation Conditioning ,Eye Diseases ,Lymphoma ,Risk Factors ,Chronic Disease ,Graft vs Tumor Effect ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Allografts - Abstract
Allogeneic haematopoietic stem cell transplantation is an effective treatment option for chemotherapy-refractory or relapsed haematological malignancies such as leukaemias and lymphomas. After conditioning with chemotherapy with or without total body irradiation, donor cells are infused to reconstitute haematopoiesis. Donor-derived immune cells induce immune reactions to control or eradicate the underlying disease, thereby going beyond the effect of chemotherapy. This graft-versus-tumour effect (GvT) is often accompanied by detrimental graft-versus-host reactions (graft-versus-host disease, GvHD), which substantially influence the mortality and morbidity after transplantation. The balance between GvHD and GvT, implementing various parameters such as donor selection, stem cell source, conditioning, immune reconstitution and immunosuppressive regimens, represents the challenge in the field of allogeneic stem cell transplantation.
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- 2015
9. [Hematopoietic stem cell transplantation: bone marrow and blood stem cells]
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M, von Bergwelt-Baildon, U, Holtick, M J, Hallek, and C, Scheid
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Evidence-Based Medicine ,Treatment Outcome ,Multiple Organ Failure ,Hematopoietic Stem Cell Transplantation ,Humans - Abstract
The number of hematopoietic stem cell transplantations is continuously increasing. On the one hand reduced intensity conditioning and improved supportive therapies allow for transplantations in patients with significant comorbidities and up to their eighth decade of life. Due to this development the number of complex and critically ill patients in need of intensive care is constantly growing. Recent developments in general critical care such as sepsis bundles and non-invasive ventilation contribute to a better outcome of these patients. However, treatment algorithms that identify patients potentially benefitting from intensive care but also reduce overtreatment of moribund patients represent a central multidisciplinary challenge not only for the treating transplant physician and intensivist.
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- 2014
10. Stammzelltransplantation – Periphere Zellen vs. Knochenmarkzellen
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U Holtick
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Oncology - Published
- 2016
11. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease
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J J, Scarisbrick, P, Taylor, U, Holtick, Y, Makar, K, Douglas, G, Berlin, E, Juvonen, S, Marshall, and Mary, Drake
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medicine.medical_specialty ,Skin Neoplasms ,medicine.medical_treatment ,education ,Graft vs Host Disease ,Dermatology ,Disease ,law.invention ,030207 dermatology & venereal diseases ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,Photopheresis ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,Internal medicine ,Extracorporeal Photopheresis ,Medicine ,Humans ,Evidence-Based Medicine ,Dose-Response Relationship, Drug ,business.industry ,Cutaneous T-cell lymphoma ,Evidence-based medicine ,Reference Standards ,medicine.disease ,Peripheral T-cell lymphoma ,3. Good health ,Surgery ,Lymphoma, T-Cell, Cutaneous ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,business - Abstract
Extracorporeal photopheresis (ECP) has been used for over 30 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic graft-versus-host disease (cGVHD). The lack of prospective randomized trials has led to different centres having different patient selection criteria, treatment schedules, monitoring protocols and patient assessment criteria. ECP for CTCL and cGVHD is available only at six specialized centres across the U.K. In the recent Improving Outcomes Guidance the National Institute for Health and Clinical Excellence endorsed the use of ECP for CTCL and because of the complexity of treatment supported its use in specialized centres and also suggested the need for expansion of this service. In 2005 consultants and senior nurses from all U.K. sites and from Scandinavia formed a Photopheresis Expert Group. This group's first aim was to produce a consensus statement on the treatment of CTCL and cGVHD with ECP using evidence-based medicine and best medical practice, in order to standardize ECP eligibility, assessment and treatment strategies across the U.K.
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- 2008
12. Deregulation of immunoglobulin gene transcription in the Hodgkin-Reed Sternberg cell line L1236
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D, Re, A, Staratschek-Jox, U, Holtick, V, Diehl, and J, Wolf
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Gene Rearrangement ,Genes, Immunoglobulin ,Transcription, Genetic ,Genes, Reporter ,Tumor Cells, Cultured ,Humans ,Reed-Sternberg Cells ,Promoter Regions, Genetic ,Hodgkin Disease - Abstract
Hodgkin-Reed Sternberg (H-RS) cells harbour clonal immunoglobulin gene (Ig) rearrangements in almost all cases of classical Hodgkin's disease but lack Ig gene expression. In the H-RS cell line L1236, a somatic mutation of the Ig heavy-chain gene promoter octamer motif has been described as a putative reason for absence of Ig gene expression. We addressed transcriptional activity of this mutated promoter by performing reporter gene studies and gel retardation assays. The results showed that the mutation outside the coding region of the rearranged Ig gene in L1236 cells leads to downregulation of Ig gene expression in H-RS cells.
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- 2001
13. Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells
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D, Re, M, Müschen, T, Ahmadi, C, Wickenhauser, A, Staratschek-Jox, U, Holtick, V, Diehl, and J, Wolf
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Adult ,Adolescent ,Genes, Immunoglobulin ,Transcription, Genetic ,3T3 Cells ,Middle Aged ,Hodgkin Disease ,DNA-Binding Proteins ,Mice ,Trans-Activators ,Tumor Cells, Cultured ,Animals ,Humans ,RNA, Messenger ,Reed-Sternberg Cells ,Octamer Transcription Factor-2 ,Aged ,Transcription Factors - Abstract
Hodgkin and Reed Sternberg (H-RS) cells represent the malignant cells in classical Hodgkin's disease. Although derived from germinal center B cells, they do not express surface immunoglobulin. This has been explained by the presence of crippling mutations within the immunoglobulin genes in numerous cases of Hodgkin's disease. As immunoglobulin gene expression in B cells requires an interaction between octamer sites and the transactivating factors Oct-2 and Bob-1, this study addresses the expression of the transcription factors Oct-2 and Bob-1 in H-RS cells. In Hodgkin's disease-derived cell lines, low levels of Oct-2 transcripts but no Oct-2 protein were detected. Transcripts of Bob-1, a B-cell-specific co-factor of Oct-2, could not be observed in these cell lines. Absence of Oct-2 and Bob-1 protein expression in primary H-RS cells was demonstrated by performing immunohistochemistry in 20 cases of classical Hodgkin's disease. H-RS cells stained negative for both proteins in all of the cases analyzed. In conclusion, absence of functional Oct-2 and Bob-1 cells represents a novel mechanism for immunoglobulin gene deregulation in H-RS cells. Lack of Oct-2 and Bob-1 points to a defect in transcription machinery in H-RS cells and is associated with lack of immunoglobulin gene expression in these cells.
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- 2001
14. P10.01 Nutritional and immunometabolic measures for risk assessment in allogeneic hematopoietic stem cell transplantation
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S Theurich, M von Bergwelt-Baildon, M Funk, K Althoff, S Leitzke, U Holtick, C Scheid, D Cordas dos Santos, S Oganesian, and H Thurisch
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2024
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15. Hope for motherhood: pregnancy after allogeneic hematopoietic cell transplantation (a national multicenter study).
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Sockel K, Neu A, Goeckenjan M, Ditschkowski M, Hilgendorf I, Kröger N, Ayuk FA, Stoelzel F, Middeke JM, Eder M, Bethge W, Finke J, Bertz H, Kobbe G, Kaufmann M, Platzbecker U, Beverungen D, Schmid C, von Bonin M, Egger-Heidrich K, Heberling L, Trautmann-Grill K, Teipel R, Bug G, Tischer J, Fraccaroli A, Fante M, Wolff D, Luft T, Winkler J, Schäfer-Eckart K, Scheid C, Holtick U, Klein S, Blau IW, Burchert A, Wulf G, Hasenkamp J, Schwerdtfeger R, Kaun S, Junghanss C, Wortmann F, Winter S, Neidlinger H, Theuser C, Beyersmann J, Bornhaeuser M, Schmeller S, and Schetelig J
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- Humans, Female, Pregnancy, Adult, Young Adult, Adolescent, Registries, Transplantation, Homologous, Infant, Newborn, Live Birth, Pregnancy Outcome, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation
- Abstract
Abstract: Improved long-term survival rates after allogeneic hematopoietic cell transplantation (alloHCT) make family planning for young adult cancer survivors an important topic. However, treatment-related infertility risk poses challenges. To assess pregnancy and birth rates in a contemporary cohort, we conducted a national multicenter study using data from the German Transplant Registry, focusing on adult women aged 18 to 40 years who underwent alloHCT between 2003 and 2018. Of 2654 women who underwent transplantation, 50 women experienced 74 pregnancies, occurring at a median of 4.7 years after transplant. Fifty-seven of these resulted in live births (77%). The annual first birth rate among HCT recipients was 0.45%, which is >6 times lower than in the general population. The probability of a live birth 10 years after HCT was 3.4%. Factors associated with an increased likelihood of pregnancy were younger age at alloHCT, nonmalignant transplant indications, no total body irradiation or a cumulative dose of <8 Gy, and nonmyeloablative/reduced-intensity conditioning. Notably, 72% of pregnancies occurred spontaneously, with assisted reproductive technologies used in the remaining cases. Preterm delivery and low birth weight were more common than in the general population. This study represents the largest data set reporting pregnancies in a cohort of adult female alloHCT recipients. Our findings underscore a meaningful chance of pregnancy in alloHCT recipients. Assisted reproductive technologies techniques are important and funding should be made available. However, the potential for spontaneous pregnancies should not be underestimated, and patients should be informed of the possibility of unexpected pregnancy despite reduced fertility. Further research is warranted to understand the impact of conditioning decisions on fertility preservation., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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16. How to optimize the CAR-T Cell therapy process? A group concept mapping analysis of preconditions for a frictionless process from a German multistakeholder perspective.
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Siefen AC, Kurte MS, Jakobs F, Teichert M, von Tresckow B, Reinhardt HC, Holtick U, Atta J, Jehn C, Sala E, Warnecke A, Hänel M, Scheid C, and Kron F
- Abstract
Introduction: Treatment with chimeric antigen receptor T (CAR-T) cells involves a large number of interdisciplinary stakeholders and is associated with complex processes ranging from patient-specific production to follow-up care. Due to the complexity, maximum process optimization is required in order to avoid efficiency losses. This study aimed at systematically determining the preconditions for a frictionless flow of the CAR-T process by surveying the stakeholders involved., Methods: A Group Concept Mapping (GCM) analysis, a mixed-methods participatory research, was conducted. CAR-T experts from different professional backgrounds went through three steps: 1) Brainstorming relevant aspects (statements) for a frictionless process, 2) Sorting the collected statements based on their similarity, and 3) Rating the importance and feasibility of each statement. A cluster map reflecting the overarching topics was derived, and mean ratings per statement and cluster were calculated., Results: Overall, 20 CAR-T experts participated. A total of 80 statements were collected, resulting in a map of the following 10 clusters (mean importance/feasibility): Information for patients and physicians (4.16/3.77), Supportive network (4.03/3.53), Eligibility of patients (4.41/3.63), Evidence, transparency and communication (4.01/3.33), Paperwork (4.1/2.52), Interface with pharmaceutical manufacturer (4.03/2.85), Reimbursement (4.29/2.31), Quality Management (4.17/3.18), Infrastructure of CAR-T clinics (4.1/2.93), and Patient-oriented processes (4.46/3.32)., Discussion: The 80 statements underlined the complex and manifold nature of the CAR-T treatment process. Our results reflect the first step in overcoming hurdles: identifying potential hurdles and required preconditions. Decision-makers and stakeholders can use the results to derive strategies and measures to further promote a frictionless process., Competing Interests: A-CS, MK, and FK are employees of VITIS Healthcare Group, which was sponsored by Gilead Sciences GmbH in connection with the development of this manuscript. FJ received consulting fees or honorarium for participation on an Advisory Board from Alexion, Cerus, Noscendo, Novartis, Pfizer, Seagen. BT is an advisor or consultant for Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag GmbH, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Roche, Sobi and Takeda; has received honoraria from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Lilly, Merck Sharp & Dohme, Novartis, Roche Pharma AG and Takeda; reports research funding from Esteve Inst, Merck Sharp & Dohme Inst, Novartis Inst, and Takeda Inst; and reports travel support from AbbVie, AstraZeneca, Gilead Kite, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis. HR received consulting and lecture fees from AbbVie, AstraZeneca, Roche, Janssen-Cilag, Novartis, Vertex and Merck. HR received research funding from Gilead and AstraZeneca. HR is a co-founder of CDL Therapeutics GmbH. UH reports honoraria/consultancies from BMS, Kite/Gilead, Miltenyi Biotec, and Novartis. CJ reports honoraria/consultancies from Gilead/Kite, BeiGene, Janssen, and BMS. ES reports honoraria/consultancies from MSD, BMS, Jazz Pharmaceutical, Kite Gilead, Therakos Mallinckrodt. AW reports honoraria from Kite/Gilead and BMS. MH is an advisor or consultant for Pfizer, Incyte, Sanofi/Aventis, Roche, Amgen, Sobi, Janssen, Sobi, BMS, Kite/Gilead. MH reports honoraria from Sobi, Novartis, Gilead, Falk Foundation, BMS. CS received honoraria/travel support from Amgen, BMS, MSD, Janssen, Pierre Fabre, Sanofi, Gilead. CS reports research funding from Janssen, Novartis, BMS, and Takeda; has received honoraria/travel support from Abbvie and Roche. MT has received honoraria from Bristol Myers Squibb and Janssen Cilag. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Gilead Sciences GmbH. The funder had the following involvement in the study: Representatives of the funder participated in the Group Concept Mapping survey. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Siefen, Kurte, Jakobs, Teichert, von Tresckow, Reinhardt, Holtick, Atta, Jehn, Sala, Warnecke, Hänel, Scheid and Kron.)
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- 2024
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17. Consistent FFP2-masking as part of reducing viral respiratory infections on medical wards for allogeneic hematopoietic stem cell transplantation.
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Richardson T, Schütte D, Feyer K, Grass L, Hallek M, Scheid C, Simon F, Braun T, Fürstenau M, Gödel P, and Holtick U
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- Humans, Male, Female, Middle Aged, Retrospective Studies, Adult, Transplantation, Homologous adverse effects, Aged, SARS-CoV-2 isolation & purification, Incidence, Hematopoietic Stem Cell Transplantation adverse effects, COVID-19 prevention & control, COVID-19 epidemiology, Respiratory Tract Infections prevention & control, Respiratory Tract Infections virology, Respiratory Tract Infections epidemiology, Masks
- Abstract
Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are highly susceptible to infections. The consequent use of masks on wards for allo-HSCT has been controversial in the past decades and was not common before the COVID-19 pandemic. We retrospectively compared incidence and outcomes of viral respiratory infections during allo-HSCT on our specialized ward between 01/2018 and 09/2020 to the era of FFP2 masking between 10/2020 and 10/2022 covering similar seasons of the year. Each group consisted of 150 matched patients. The usage of FFP2 masks reduced the incidence of viral respiratory infections from 22.1 to 2.1% (p < 0.005). This reduced the time on ward from a median of 26 days to 23.5 days (p = 0.002). It also resulted in less use of CT-scans (p = 0.003) and bronchoalveolar lavage procedures (p = 0.057). Median time to proof of infection was 21 days after admission in both groups. No difference was detected in progression free survival, hospital survival or non-relapse mortality (p = 0.78). Our retrospective results indicate that FFP2 masks worn by patients and hospital staff may help to significantly reduce the incidence of viral respiratory infections, including COVID-19, shorten the in-hospital time, and reduce costs without affecting survival., (© 2024. The Author(s).)
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- 2024
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18. The life threat in hematopoietic allogeneic stem cell transplantation - an interview and focus group study on health care professionals' perspectives.
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Reimer A, Ley M, Schepers C, Pralong A, Schoerger B, Voltz R, Hallek M, Herling M, Holtick U, and Simon ST
- Abstract
Understanding healthcare professionals' (HCPs) experiences with patients undergoing hematopoietic allogeneic stem cell transplantation (allo-HSCT) is crucial, given its dual nature of offering a hope for cure which on the other hand is accompanied by a high risk for morbidity and mortality. Yet, how HCPs experience their patients' existential threats remains unexplored. Qualitative thematic content analysis was employed to comprehend these experiences. This involved conducting three focus groups and 11 individual in-depth interviews with nurses and hematologists. We found that HCPs struggled to balance curative goals and the therapy's risks, while attempting to maintain their patients' hopes. The unpredictability of patient trajectories and their suffering burdened HCPs. Despite occasional disagreements within the team, (inter-)professional exchanges remained a crucial ressource, especially in addressing the patients' potential life threat. Team meetings and palliative care specialist supervisions were emphasized as vital for managing these challenges. HCPs sought support in communicating with patients about death-related issues and managing the transition from a curative to a palliative goal of care. Our research underscores the need for targeted support for HCPs and lays a groundwork for addressing their challenges. Trial registration number DRKS00027290 (German Clinical Trials Register). Date of trial registration January 10th, 2022., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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19. Final outcomes analysis of the cell product SQZ-PBMC-HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration.
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Weaver AN, Iams WT, Park JC, Mita M, Holtick U, Gordon MS, Rodabaugh KJ, Dhani N, Neupane P, Taylor M, Amanda Duvall E, Jennings J, Miselis NR, Loughhead S, Warren MS, Bernstein H, Klussmann JP, Baranda J, and Jimeno A
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- Humans, Female, Middle Aged, Male, Papillomavirus E7 Proteins immunology, Lymphocytes, Tumor-Infiltrating immunology, Aged, Oncogene Proteins, Viral immunology, Cancer Vaccines therapeutic use, Cancer Vaccines administration & dosage, Cancer Vaccines immunology, Neoplasms immunology, Neoplasms pathology, Neoplasms mortality, Adult, Leukocytes, Mononuclear immunology, Repressor Proteins, CD8-Positive T-Lymphocytes immunology, Human papillomavirus 16 immunology, Papillomavirus Infections complications, Papillomavirus Infections immunology, Papillomavirus Infections virology
- Abstract
Cancer vaccines strive to induce robust, antigen-targeted, T-cell-mediated immune responses but have struggled to produce meaningful regression in solid tumors. An autologous cell vaccine, SQZ-PBMC-HPV, was developed by SQZ Biotechnologies using microfluidic squeezing technology to load PBMCs with HPV16 E6 and E7 antigens in HLA-A*02+ patients. The SQZ-PBMC-HPV-101 Phase 1 trial (NCT04084951) enrolled patients with incurable HPV16+ cancers. Here, we present a post hoc analysis of the relationship between Posttreatment CD8+ T cell infiltration and patient outcomes. SQZ-PBMC-HPV was administered as monotherapy every 3 weeks. Tumor samples were collected pre-dose and post-dose 4 weeks after treatment start. Biomarkers including CD8, MHC-I, E6, E7, GZMB, and Ki67 were evaluated by immunohistochemistry, immunofluorescence, and RNA in situ hybridization, and were correlated with clinical response, survival, and drug product composition. Eighteen patients had paired pre- and post-dose biopsies. Six (33%) had an increase in CD8+ T cell density in tumor parenchyma between screening and C2D8. Patients with increased CD8+ T cell density had improved disease control rate (66.7% vs 16.7%) and median overall survival (606.5 days vs 170.0 days, p = 0.0078). Drug product was significantly enriched for higher T cells and lower monocytes in the increased CD8+ T cell density group. In patients with incurable HPV16+ solid tumors treated with SQZ-PBMC-HPV, an increase in CD8+ T cell density within the tumor parenchyma was associated with superior disease control rate and overall survival. The product composition for patients with increased CD8+ T cell density was enriched for T cells., (© 2024 Wiley Periodicals LLC.)
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- 2024
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20. Post-transplant-cyclophosphamide and short-term Everolimus as graft-versus-host-prophylaxis in patients with relapsed/refractory lymphoma and myeloma-Final results of the phase II OCTET-EVER trial.
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Richardson T, Scheid C, Herling M, Frenzel LP, Herling C, Aguilar MRC, Theurich S, Hallek M, and Holtick U
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- Humans, Female, Middle Aged, Male, Adult, Aged, Recurrence, Lymphoma therapy, Lymphoma mortality, Lymphoma diagnosis, Treatment Outcome, Immunosuppressive Agents therapeutic use, Immunosuppressive Agents administration & dosage, Transplantation, Homologous, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Everolimus administration & dosage, Everolimus therapeutic use, Cyclophosphamide therapeutic use, Cyclophosphamide administration & dosage, Multiple Myeloma therapy, Multiple Myeloma mortality, Multiple Myeloma diagnosis, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods
- Abstract
Background: Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response., Methods: We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD., Results: Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years., Conclusions: Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2024
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21. Insulin eye drops for severe refractory chronic ocular graft-versus-host disease.
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Tahmaz V, Menghesha L, Stern ME, Holtick U, Scheid C, and Steven P
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- Adult, Female, Humans, Male, Middle Aged, Chronic Disease, Eye Diseases etiology, Eye Diseases drug therapy, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease drug therapy, Insulin administration & dosage, Ophthalmic Solutions therapeutic use
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- 2024
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22. 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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Bonig H, Verbeek M, Herhaus P, Braitsch K, Beutel G, Schmid C, Müller N, Bug G, Döring M, von Stackelberg A, Tischer J, Ayuk F, Wulf G, Holtick U, Pfeffermann LM, Jahrsdörfer B, Schrezenmeier H, Kuci S, Kuci Z, Zens A, Tribanek M, Zeiser R, Huenecke S, and Bader P
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- 2024
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23. Long-term remission in a patient with relapsed Richter's transformation treated with CD19-directed chimeric antigen-receptor T-cells after allogeneic stem cell transplantation.
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Kutsch N, Gödel P, Voltin CA, Hallek M, Scheid C, Borchmann P, and Holtick U
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- Humans, Female, Middle Aged, Treatment Outcome, Receptors, Chimeric Antigen, Recurrence, Combined Modality Therapy, Piperidines therapeutic use, Receptors, Antigen, T-Cell genetics, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse diagnosis, Hematopoietic Stem Cell Transplantation, Transplantation, Homologous, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects, Remission Induction, Antigens, CD19 immunology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
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Patients with Richter's transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL-RT) face a dismal prognosis. A 51-year-old female patient diagnosed with CLL with deletion (17p) in 2009. CLL treatment included chemoimmunotherapy and targeted substances. DLBCL-RT was diagnosed in November 2016. After receiving an allogeneic hematopoietic stem cell transplantation, she relapsed in September 2019 and tisagenlecleucel was infused in December 2019. Cytokine release syndrome grade 2 was treated with two doses of tocilizumab and the patient was started on 140 mg ibrutinib in February 2020. Our patient remains in remission up to 4 years after CAR T-cell treatment., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2024
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24. Multiparametric Monitoring of Disease Progression in Contemporary Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy Initiating Tafamidis Treatment.
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Ney S, Gertz RJ, Pennig L, Nies RJ, Holtick U, Völker LA, Wunderlich G, Seuthe K, Hohmann C, Metze C, Nähle CP, von Stein J, Brüwer M, Ten Freyhaus H, and Pfister R
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Background: Recently, a disease modifying therapy has become available for transthyretin amyloid cardiomyopathy (ATTR-CM). A validated monitoring concept of treatment is lacking, but a current expert consensus recommends three clinical domains (clinical, biomarker and ECG/imaging) assessed by several measurable features to define disease progression., Methods: We retrospectively analyzed data of wild-type ATTR-CM patients initiating tafamidis therapy assessed within our local routine protocol at baseline and 6-months follow-up with respect to the frequency of values beyond the proposed thresholds defining disease progression. Additionally, associations of cardiac magnetic resonance (CMR) tomography with clinical domains were examined within a subgroup., Results: Sixty-two ATTR-CM patients were included (88.7% male, mean age 79 years). In total, 16.1% of patients had progress in the clinical and functional domain, 33.9% in the biomarker domain and 43.5% in the imaging/electrocardiography (ECG) domain, with the latter driven by deterioration of the diastolic dysfunction grade and global longitudinal strain. In total, 35.5% of patients showed progress in none, 35.5% in one, 29.0% in two and no patient in three domains, the latter indicating overall disease progression. A subgroup analysis of twenty-two patients with available baseline and follow-up CMR data revealed an increase in CMR-based extracellular volume by more than 5% in 18.2% of patients, with no significant correlation with progress in one of the clinical domains., Conclusions: We provide first frequency estimates of the markers of disease progression according to a recent expert consensus statement, which might help refine the multiparametric monitoring concept in patients with ATTR-CM.
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- 2024
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25. Clinical and Economic Burden Associated With Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation in Germany.
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Holtick U, Quignot N, Kapso-Kapnang R, Reichenbach D, Kelly M, Burrell A, Zhang X, and Thiruvillakkat K
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- Adult, Humans, Retrospective Studies, Financial Stress, Hospitalization, Acute Disease, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease diagnosis, Graft vs Host Disease epidemiology, Graft vs Host Disease etiology
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Background: Acute graft-vs-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), yet there are limited data on the clinical and economic burden of aGVHD in Germany. This real-world study aimed to evaluate clinical and economic outcomes among patients in Germany with or without aGVHD after allo-HSCT., Methods: This retrospective cohort study used administrative claims extracted from the German statutory health insurance database. Eligible adult patients underwent allo-HSCT between 1 January 2009 and 31 December 2017 for any hematological malignancy. Clinical (severe infections and mortality) and economic (health care resource use [HCRU] and costs) outcomes were compared in "aGVHD" patients and "no GVHD" patients. Propensity score matching (1:1) was used to balance covariates between the aGVHD and no GVHD groups., Results: After propensity score matching, 95 aGVHD and 95 no GVHD patients were included in the analysis. The aGVHD group had significantly higher odds of mortality than the no GVHD group (odds ratio [OR] 2.2; 95% CI 1.2-4.0). Odds of severe infection were similar between the 2 groups (OR 1.7; 95% CI 0.9-3.3). Patients in the aGVHD group had significantly more overnight hospitalizations per patient-year (mean [SD]: 3.7 [3.0] and 2.7 [2.5], P = .029), and total direct costs were 1.6-fold higher than those in the no GVHD group., Conclusion: Among patients who underwent allo-HSCT, aGVHD was associated with significantly higher mortality, HCRU, and costs, highlighting the need for effective prophylaxis and treatment options to prevent or reduce the incidence of aGVHD., Competing Interests: Declaration of competing interest U.H. has received honoraria for consultancies from CSL Behring and Novartis and research grants from Novartis. N.Q. and R.K. report consulting fees paid to Certara from CSL Behring. D.R., M.K., X.Z., and K.T. are employees of CSL Behring. A.B. has received consulting fees from CSL Behring, Neumentum, and Healx., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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26. Long-Term Survivors after Failure of Chimeric Antigen Receptor T Cell Therapy for Large B Cell Lymphoma: A Role for Allogeneic Hematopoietic Cell Transplantation? A German Lymphoma Alliance and German Registry for Stem Cell Transplantation Analysis.
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Derigs P, Bethge WA, Krämer I, Holtick U, von Tresckow B, Ayuk F, Penack O, Vucinic V, von Bonin M, Baldus C, Mougiakakos D, Wulf G, Schnetzke U, Stelljes M, Fante M, Schroers R, Kroeger N, and Dreger P
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- Humans, Retrospective Studies, Neoplasm Recurrence, Local etiology, Registries, Recurrence, Survivors, Receptors, Chimeric Antigen, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Large B-Cell, Diffuse therapy
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The outcome of patients with large B cell lymphoma (LBCL) who relapse or progress after CD19-directed chimeric antigen receptor T cell therapy (CAR-T) administered as salvage therapy beyond the second treatment line is poor. However, a minority of patients become long-term survivors despite CAR-T failure. The German Lymphoma Alliance (GLA) has proposed a hierarchical management algorithm for CAR-T failure in LBCL, aimed at allogeneic hematopoietic cell transplantation (alloHCT) as definite therapy in eligible patients. The purpose of this study was to investigate characteristics, relapse patterns, and management strategies in long-term survivors after CAR-T failure, with a particular focus on the feasibility and outcome of alloHCT. This was a retrospective analysis of all evaluable patients with a relapse/progression event (REL) observed in a previously reported GLA sample between November 2018 and May 2021. REL occurred in 214 of 356 patients (60%) who underwent CAR-T for LBCL in the previous GLA study. An evaluable dataset was available for 143 of these 214 patients (67%). Twenty-six of 143 patients (18%) survived 12 months or longer from REL, 109 (76%) died within the first year after REL, and 8 (6%) were alive but had not reached the 12-month landmark. Long-term survivors had more favorable pre-CAR-T features, had a longer interval between CAR-T and REL, and had more often received a tumor biopsy after CAR-T failure, whereas the choice of the first salvage regimen had no impact. AlloHCT was feasible in 40 of 53 patients (75%) intended and resulted in a 12-month post-transplantation overall survival of 36% in those patients who underwent transplantation with sensitive or untreated REL. AlloHCT after CAR-T failure in LBCL is feasible and may be an important contributor to long-term survival, although selection bias must be taken into account. Thus, alloHCT should be considered as a reasonable treatment option for eligible patients in this setting. However, because the overall outlook after CAR-T failure remains poor, novel effective therapeutic approaches are needed, either to allow long-term disease control per se or to improve the preconditions for successful alloHCT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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27. Torque teno virus-DNA load as individual cytomegalovirus risk assessment parameter upon allogeneic hematopoietic stem cell transplantation.
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Spiertz A, Tsakmaklis A, Farowski F, Knops E, Heger E, Wirtz M, Kaiser R, Holtick U, Vehreschild MJGT, and Di Cristanziano V
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- Humans, Cytomegalovirus, DNA, Viral, Risk Assessment, Viral Load, Torque teno virus genetics, Cytomegalovirus Infections diagnosis, Cytomegalovirus Infections etiology, Hematopoietic Stem Cell Transplantation adverse effects
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Background: Immune recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) decisively influences the occurrence of opportunistic infections, one of the leading causes of death among this group of patients. Yet, today, there are no laboratory parameters mirroring immune function sufficiently. Torque teno virus (TTV) has already proven itself as a functional immune marker in other settings., Aims: In this analysis, we investigated whether monitoring of TTV-DNA load in whole blood is able to provide additional information on the capacity of the immune system to control cytomegalovirus (CMV) replication in allo-HSCT recipients., Methods: Whole blood samples from 59 patients were collected upon allo-HSCT (between Day -7 and +10), on Day +14, +21, +28, +56, +90, and +365 post-transplant. TTV-DNA loads and other relevant clinical information were correlated with the risk of CMV infections or reactivations, defined by evidence of viral replication in blood., Results: CMV serostatus of the recipient and a TTV load below 1000 copies/mL upon allo-HSCT were significantly associated with an increased incidence of CMV infection or reactivation., Conclusions: Quantification of TTV load in the early phase of allo-HSCT procedure could provide additional information in order to identify patients at risk for CMV infection or reactivation., (© 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2023
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28. 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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Bonig H, Verbeek M, Herhaus P, Braitsch K, Beutel G, Schmid C, Müller N, Bug G, Döring M, von Stackelberg A, Tischer J, Ayuk F, Wulf G, Holtick U, Pfeffermann LM, Jahrsdörfer B, Schrezenmeier H, Kuci S, Kuci Z, Zens A, Tribanek M, Zeiser R, Huenecke S, and Bader P
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- Child, Adult, Humans, Retrospective Studies, Acute Disease, Mesenchymal Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease drug therapy, Mesenchymal Stem Cells
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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., (© 2023. The Author(s).)
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- 2023
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29. Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial.
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Schroeder T, Stelljes M, Christopeit M, Esseling E, Scheid C, Mikesch JH, Rautenberg C, Jäger P, Cadeddu RP, Drusenheimer N, Holtick U, Klein S, Trenschel R, Haas R, Germing U, Kröger N, and Kobbe G
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- Adult, Humans, Azacitidine therapeutic use, Lenalidomide, Lymphocyte Transfusion adverse effects, Transplantation, Homologous adverse effects, Chronic Disease, T-Lymphocytes pathology, Recurrence, Leukemia, Myelomonocytic, Chronic therapy, Leukemia, Myelomonocytic, Chronic complications, Myelodysplastic Syndromes pathology, Leukemia, Myeloid, Acute, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Graft vs Host Disease drug therapy, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Azacitidine (Aza) combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide (Lena) to act synergistically with Aza/DLI to improve outcome. We, therefore, prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia. Patients were scheduled for eight cycles Aza (75 mg/m2 day 1-7), Lena (2.5 or 5 mg, days 1-21) and up to three DLI with increasing T-cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of myelodysplastic syndromes (n=24), acute myeloid leukemia (n=23) or chronic myelomonocytic leukemia (n=3) received a median of seven (range, 1-8) cycles including 14 patients with 2.5 mg and 36 with 5 mg Lena daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lena dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade 2-4 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lena can be safely added to Aza/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse (clinicaltrials gov. Identifier: NCT02472691).
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- 2023
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30. A German-Wide Systematic Study on Mobilization and Collection of Hematopoietic Stem Cells in Poor Mobilizer Patients with Multiple Myeloma prior to Autologous Stem Cell Transplantation.
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Bittrich M, Kriegsmann K, Tietze-Stolley C, Movassaghi K, Grube M, Vucinic V, Wehler D, Burchert A, Schmidt-Hieber M, Rank A, Dürk HA, Metzner B, Kimmich C, Hentrich M, Kunz C, Hartmann F, Khandanpour C, de Wit M, Holtick U, Kiehl M, Stoltefuß A, Kiani A, Naumann R, Scholz CW, Tischler HJ, Görner M, Brand F, Ehmer M, and Kröger N
- Abstract
Introduction: In patients with a clinical indication for autologous hematopoietic stem cell transplantation (ASCT), sufficient mobilization of CD34
+ precursor cells into peripheral blood is essential to ensure adequate hematopoietic stem cell (HSC) collection prior to intensive therapy. However, with standard granulocyte-colony stimulating factor (G-CSF)-based mobilization schemes, an important minority of patients fail to mobilize sufficient (e.g., >10/µL) CD34+ cell counts into the peripheral blood and are considered as poor mobilizers (PM). Because failure to achieve sufficient CD34+ cell mobilization can negatively affect important clinical treatment endpoints, the use of plerixafor (PLX) was approved to increase CD34+ mobilization in PM patients., Methods: The German non-interventional, multicenter, open-label, prospective OPTIMOB study evaluated HSC mobilization strategies prior to planned ASCT in adult patients with hematologic malignancies (lymphomas or multiple myeloma [MM]) focusing on PM patients. PM patients were defined as follows: (1) never achieving ≥20 CD34+ cells/µL before 1st apheresis, (2) receiving PLX at any timepoint of mobilization, (3) their initially planned stem cell yield had to be reduced, or (4) they had not received apheresis due to low CD34+ count in peripheral blood., Results: 168 of 475 MM patients (35%) participating in the OPTIMOB study were classified as PM, and 155 of them (92%) received PLX (PM+PLX) during the study. PM patients were 40-78 years old, slightly more often male ( n = 97, 58%), mostly newly diagnosed ( n = 146, 87%) and received highly individualized previous treatments. Ninety-four of the PMs underwent chemotherapy mobilization (65%), and 51 patients (35%) received steady-state mobilization with G-CSF only during 1st mobilization attempt. 92% of the total PM population ( n = 155) underwent apheresis, 78% of them ( n = 117) achieved >2.0 × 106 CD34+ cells/kg body weight on the 1st day of apheresis. PM+PLX had a higher median total collection result than those PM patients without PLX support (7.2 vs. 5.7 × 106 CD34+ cells/kg body weight). In total, ASCT was performed in 136 PM+PLX (88%) versus 8 PM-PLX patients (62%)., Conclusion: The OPTIMOB study showed that a considerable proportion of adult MM patients in Germany are PMs. Even though most of PMs were supported with PLX in the OPTIMOB study, PM-PLX also successfully mobilized HSCs, allowing ASCT in majority of all PMs. However, further analyses are required for treatment optimization in PMs., Competing Interests: M.B. received honoraria for advisory board and consultancy activities from Bristol-Myers Squibb, Sanofi-Aventis Deutschland GmbH, and GlaxoSmithKline GmbH & Co. KG; research funding from Bristol-Myers Squibb (Celgene), Otsuka Pharmaceuticals, Sanofi, Chugai Pharma, AbbVie, AMGEN, and Janssen; and owns shares from AbbVie. K.K. received research funding from Bristol-Myers Squibb and Sanofi-Aventis Deutschland GmbH. C.T.S. received honoraria from Sanofi. M.G. (Matthias Grube) received honoraria from Sanofi, Janssen, and Bayer. V.V. received honoraria from Sanofi, Bristol-Myers Squibb, Novartis, Amgen, and Janssen. D.W. received honoraria for advisory board activities and travel support from Sanofi. A.B. received honoraria from Incyte and AOP Orphan and scientific support from AOP Orphan. M.S.H. received honoraria for consultancy activities from Celgene GmbH, Amgen GmbH, Kite/Pharma Gilead, Sanofi-Aventis Deutschland GmbH, GlaxoSmithKline GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KG, Shionogi GmbH, and Stemline Therapeutics (no individual payment) and financial support of educational meetings from Janssen-Cilag GmbH, Takeda Pharma Vertrieb GmbH & Co. KG, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, Vifor Pharma Deutschland GmbH, and Celgene GmbH (no individual payment). Additionally, M.S.H. participated in different clinical trials supported by the industry (including the OPTIMOB study). C. K. (Christoph Kimmich) received honoraria from Amgen, Janssen, Kite/Pharma Gilead, Takeda, GlaxoSmithKline GmbH & Co., and Sanofi-Aventis Deutschland GmbH, as well as travel support from Janssen and Kite/Pharma Gilead. M.H. received lecture fees from Amgen, AstraZeneca, Eusa Pharma, Celgene, Janssen, Jazz Pharma, and Takeda, and served on advisory boards of Amgen, Eusa Pharma, Janssen, and Sanofi. C.K. (Christian Kunz) received honoraria for advisory board activities from AbbVie, Sanofi, Bristol-Myers Squibb, and Amgen, as well as financial support for congress participation from AbbVie, Amgen, and Bristol-Meyer Squibb. C.K. (Cyrus Khandanpour) received honoraria and research funding from Sanofi, Bristol-Myers Squibb, AstraZeneca, Novartis, Amgen, and Janssen. M.W. received honoraria for lectures from AstraZeneca, Novartis, Ispen, Roche, Janssen, Sanofi, Medac, Takeda, and Pierre Fabre; travel support from AstraZeneca, AbbVie, and Pfizer; and research funding from AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Janssen, Takeda, MSD, Boehringer, Pierre Fabre, Amgen, Genzyme, and MorphoSys. U.H. received honoraria from Sanofi and Amgen. R.N. received honoraria for consultancy activities from AvenCell (formerly Cellex Patient Treatment GmbH), Simon Kucher & Partners Strategy & Marketing Consultants GmbH, and Takeda; honoraria for advisory board activities from Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, Oncopeptides, Bristol-Myers Squibb (Celgene), Janssen, Gilead, and Amgen; honoraria for lectures from Forum Medizin Fortbildung (FOMF) and Bildungsinstitut für Gesundheitsberufe Südwestfalen in Siegen (BIGS) GmbH; and honoraria for authorship from Elsevier. C.W.S. received honoraria from Bristol-Myers Squibb, Celgene, Daiichi Sankyo, GILEAD, Hexal, Incyte, Janssen, Lilly, MSD, Merck Serono, Miltenyi Biotec, Novartis, Pfizer, Roche, and Takeda. H.J.T. received honoraria from Sanofi, Bristol-Myers Squibb, and Takeda. F.B. and M.E. are employed by Sanofi-Aventis Deutschland GmbH and may hold stock and/or stock options in the company. N.K. received honoraria and research funding from Sanofi, Bristol-Myers Squibb, Neovii, Novartis, Amgen, and Riemser. A.K., K.M., A.S., M.G. (Martin Görner), F.H., H.A.D., A.R., B.M., and M.K. have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)- Published
- 2023
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31. Mobilization and Hematopoietic Stem Cell Collection in Poor Mobilizing Patients with Lymphoma: Final Results of the German OPTIMOB Study.
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Kriegsmann K, Bittrich M, Sauer S, Tietze-Stolley C, Movassaghi K, Grube M, Vucinic V, Wehler D, Burchert A, Schmidt-Hieber M, Rank A, Dürk HA, Metzner B, Kimmich C, Hentrich M, Kunz C, Hartmann F, Khandanpour C, de Wit M, Holtick U, Kiehl M, Stoltefuß A, Kiani A, Naumann R, Scholz CW, Tischler HJ, Görner M, Brand F, Ehmer M, and Kröger N
- Abstract
Introduction: Successful mobilization and collection of peripheral hematopoietic stem cells (HSCs) are necessary for lymphoma patients eligible for myeloablative chemotherapy with subsequent autologous stem cell transplantation (ASCT). Albeit G-CSF alone or combined with chemotherapy is well-established methods for HSC mobilization, up to 40% of the patients fail to mobilize (poor mobilizer, PM). Plerixafor (PLX) is commonly used in PM patients resulting in increased migration of HSCs into peripheral blood and thus improves the collection outcome., Methods: The prospective, multicenter, open-label, non-interventional OPTIMOB study assessed mobilization and collection parameter of patients with lymphoma or multiple myeloma to get deep insights in the treatment of those patients in clinical routine focusing on PM patients. PM was defined as follows: (1) no achievement of ≥20 CD34
+ progenitor cells/µL before first apheresis, (2) PLX administration at any time point during the observational period, (3) reduction of the initially planned CD34+ progenitor cell yield as necessity due to failed mobilization or HSC collection, and (4) no performance of apheresis due to low CD34+ progenitor level. Primary objective of the study was to assess mobilization success by the proportion of PM patients achieving >2 × 106 CD34+ progenitor cells/kg body weight on the first day of apheresis. Here, the data of the lymphoma cohort are presented., Results: Out of 238 patients with lymphoma documented in the study, 32% were classified as PM. 87% of them received PLX. Demographic data revealed no obvious differences between PM and good mobilizing (GM) patients. All patients were treated highly individualized prior to mobilization. Majority of all PM patients were able to undergo apheresis (95%) and reached their individual requested CD34+ progenitor cell target (72%). 57% of the PM patients achieved >2.0 × 106 CD34+ progenitor cells/kg body weight on day 1 of apheresis and nearby 70% of them underwent ASCT. Median time to engraftment was similar in PM and GM patients of the lymphoma cohort., Conclusions: Majority of PM patients with lymphoma were successfully mobilized and underwent ASCT. Most of them received PLX during the study., Competing Interests: K.K. received research funding from Bristol Myers Squibb and Sanofi-Aventis Deutschland GmbH. M.B. received honoraria for advisory board and consultancy activities from Bristol Myers Squibb, Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, research funding from Bristol Myers Squibb (Celgene), Otsuka Pharmaceuticals, Sanofi, Chugai Pharma, Abbvie, AMGEN, and Janssen, and owns shares from Abbvie. S.S. received honoraria and research funding from Sanofi-Aventis Deutschland GmbH, Bristol Meyers Squibb, Amgen, and Janssen. C.T.-S. received honoraria from Sanofi. M.G. (Matthias Grube) received honoraria from Sanofi, Janssen, and Bayer. V.V. received honoraria from Sanofi, Bristol Myers Squibb, Novartis, Amgen, and Janssen. D.W. received honoraria for advisory board activities and travel support from Sanofi. A.B. received honoraria from Incyte and AOP Orphan and scientific support from AOP Orphan. M.S.-H. received honoraria for consultancy activities from Celgene GmbH, Amgen GmbH, Kite/Pharma Gilead, Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, Bristol Myers Squibb GmbH & Co. KG, Shionogi GmbH, Stemline Therapeutics (no individual payment) and financial support of educational meetings from Janssen-Cilag GmbH, Takeda Pharma Vertrieb GmbH & Co. KG, Novartis Pharma GmbH, Pfizer Pharma GmbH, Roche Pharma AG, Vifor Pharma Deutschland GmbH, and Celgene GmbH (no individual payment). Additionally, M.S.-H. participated in different clinical trials supported by the industry (including the OPTIMOB study). C.K. (Christoph Kimmich) received honoraria from Amgen, Janssen, Kite/Pharma Gilead, Takeda, Glaxo Smith Kline GmbH & Co, and Sanofi-Aventis Deutschland GmbH as well as travel support from Janssen and Kite/Pharma Gilead. M.H. received lecture fees by Amgen, AstraZeneca, EusaPharma, Celgene, Janssen, Jazz Pharma, and Takeda, and served on advisory boards of Amgen, EusaPharma, Janssen, and Sanofi. C.K. (Christian Kunz) received honoraria for advisory board activities from Abbvie, Sanofi, Bristol Meyer Squibb, and Amgen as well as financial support for congress participation from Abbvie, Amgen, and Bristol Meyer Squibb. C.K. (Cyrus Khandanpour) received honoraria and research funding from Sanofi, Bristol Myers Squibb, AstraZeneca, Novartis, Amgen, and Janssen. M.W. received honoraria for lectures from AstraZeneca, Novartis, Ispen, Roche, Janssen, Sanofi, Medac, Takeda, and Pierre Fabre, travel support from AstraZeneca, Abbvie, and Pfizer, and research funding from AstraZeneca, Bristol Meyer Squibb, Novartis, Phizer, Roche, Janssen, Takeda, MSD; Boehringer, Pierre Fabre, Amgen, Genzyme, and MorphoSys. U.H. received honoraria from Sanofi and Amgen. R.N. received honoraria for consultancy activities from AvenCell (formerly Cellex Patient Treatment GmbH), Simon Kucher and Partners Strategy and Marketing Consultants GmbH, and Takeda, honoraria for advisory board activities from Sanofi-Aventis Deutschland GmbH, Glaxo Smith Kline GmbH & Co. KG, Oncopeptides, Bristol Myers Squibb (Celgene), Janssen, Gilead, Amgen, honoraria for lectures from Forum Medizin Fortbildung (FOMF), Bildungsinstitut für Gesundheitsberufe Südwestfalen in Siegen (BIGS) GmbH, and honoraria for authorship from Elsevier. C.W.S. received honoraria from Bristol Myers Squibb, Celgene, Daiichi Sankyo, GILEAD, Hexal, Incyte, Janssen, Lilly, MSD, Merck Serono, Miltenyi Biotec, Novartis, Pfizer, Roche, and Takeda. H.J.T. received honoraria from Sanofi, Bristol Meyer Squibb, and Takeda. F.B. and M.E. are Employed by Sanofi-Aventis Deutschland GmbH and May Hold Stock and/or Stock Options in the Company. N.K. received honoraria and research funding from Sanofi, Bristol Myers Squibb, Neovii, Novartis, Amgen, and Riemser. A.K., K.M., A.S., M.G. (Martin Görner), F.H., H.A.D., A.R., B.M., and M.K. have no conflicts of interest to declare., (© 2023 The Author(s). Published by S. Karger AG, Basel.)- Published
- 2023
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32. Developing a supportive and palliative care intervention for patients with allogeneic stem cell transplantation: protocol of a multicentre mixed-methods study (allo-PaS).
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Pralong A, Herling M, Holtick U, Scheid C, Hellmich M, Hallek M, Pauli B, Reimer A, Schepers C, and Simon ST
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- Humans, Cross-Sectional Studies, Multicenter Studies as Topic, Quality of Life, Retrospective Studies, Surveys and Questionnaires, Research Design, Hematopoietic Stem Cell Transplantation, Palliative Care
- Abstract
Introduction: Although allogeneic stem cell transplantation (allo-SCT) is a curative treatment for many haematological malignancies, it is often associated with a high morbidity and mortality. Yet, little is known about the needs for supportive and palliative care among allo-SCT recipients. Moreover, targeted interventions that reduce symptom burden and suffering are still lacking. The present study aims to inform a supportive-palliative care intervention for patients with allo-SCT and their informal carers by exploring their experience and assessing their needs, especially their existential concerns, regarding four research topics: symptom burden and quality of life; coexistence of a chance for cure and a relevant risk of dying; change in goals of care; dying phase., Methods and Analysis: This is a descriptive mixed-methods study in progress with a convergent parallel design. Data on the four research topics will be collected and analysed separately in three steps: (1) qualitative semi-structured interviews among 20 patients, 20 informal carers and 12 healthcare providers (HCPs) and focus groups among 12-24 HCPs; (2) a quantitative cross-sectional survey with validated questionnaires and self-developed questions among 100 patients, 100 informal carers and 50 HCPs; (3) a retrospective case analysis of all deceased patients who underwent an allo-SCT between 2010 and 2019, with collection of quantitative and qualitative data. The qualitative and quantitative data sets will be finally merged for comparison and interpretation. Results will serve to develop a supportive-palliative care intervention., Ethics and Dissemination: The Ethics Commission of the Faculty of Medicine of the University of Cologne approved this study (20-1370_2). The study results will be published in peer-review journals, be presented at congresses and will be translated into clinical practice through the development of the palliative-supportive care intervention., Trial Registration Number: DRKS00027290 (German Clinical Trials Register)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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33. Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use.
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Bücklein V, Perez A, Rejeski K, Iacoboni G, Jurinovic V, Holtick U, Penack O, Kharboutli S, Blumenberg V, Ackermann J, Frölich L, Johnson G, Patel K, Arciola B, Mhaskar R, Wood A, Schmidt C, Albanyan O, Gödel P, Hoster E, Bullinger L, Mackensen A, Locke F, von Bergwelt M, Barba P, Subklewe M, and Jain MD
- Abstract
Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use., Competing Interests: VB: Amgen: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kite/Gilead: Research Funding, Honoraria; Novartis: Honoraria. KR: Kite/Gilead: Research Funding and travel support. Novartis: Honoraria. GI: Consultancy and Honoraria: Novartis, Roche, Kite/Gilead, Bristol-Myers Squibb, Abbvie, Janssen, Sandoz, Miltenyi. UH: Consultancy and Honoraria: Amgen, BMS/Celgene, CSL Behring, GSK, Janssen, Kite/Gilead, Novartis, Sanofi. OP: Honoraria or travel support: Gilead, Jazz, MSD, Novartis, Pfizer and Therakos. Research support: Incyte and Priothera. Consultancy: Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Priothera, Shionogi and SOBI. SK: Celgene/Bristol-Myers Squib: Honoraria. V Blumenberg: Novartis: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Janssen: Research Funding. PG: Travel support: Gilead. LB: Honoraria: Novartis, Celgene/BMS, Astellas, Gilead, Abbvie, Jazz Pharmaceuticals, Pfizer, Janssen; Consultancy: Novartis, Celgene/BMS, Gilead, Abbvie, Jazz Pharmaceuticals, Pfizer, Janssen; Research Funding: Jazz Pharmaceuticals, Bayer Oncology. AM: Honoraria: Novartis, Kite/Gilead, Celgene/BMS, Miltenyi Biomedicine. FL: has a scientific advisory role with Kite, a Gilead Company, Novartis, Celgene/Bristol-Myers Squibb, GammaDelta Therapeutics, Wugen, Amgen, Calibr, and Allogene; is a consultant with grant options for Cellular Biomedicine Group, Inc.; and receives research support from Kite, a Gilead Company, Novartis, and Allogene; and reports that his institution holds unlicensed patents in his name in the field of cellular immunotherapy. MvB: Consultancy, Research Funding and Honoraria: MSD Sharp & Dohme, Novartis, Roche, Kite/Gilead, Bristol-Myers Squibb, Astellas, Mologen, and Miltenyi. PB: declares having received honoraria from Amgen, BMS, Gilead, Incyte, Miltenyi Biotec, Novartis and Pfizer not related with the present article. MS: Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding. MDJ: Kite/Gilead: Consultancy/Advisory, Novartis: Consultancy/Advisory, BMS: Consultancy/Advisory, Takeda: Consultancy/Advisory. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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34. Characterization and outcome of post-transplant lymphoproliferative disorders within a collaborative study.
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Lückemeier P, Radujkovic A, Holtick U, Kurch L, Monecke A, Platzbecker U, Herling M, and Kayser S
- Abstract
Background: Post-transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that can arise after solid organ transplantation (SOT) and allogeneic hematopoietic transplantation (allo-HSCT)., Methods: In this multi-center retrospective study, we compare patient characteristics, therapies, and outcomes of PTLD after allo-HSCT and SOT. Twenty-five patients (15 after allo-HSCT and 10 after SOT) were identified who developed PTLD between 2008 and 2022., Results: Median age (57 years; range, 29-74 years) and baseline characteristics were comparable between the two groups (allo-HSCT vs SOT), but median onset of PTLD was markedly shorter after allo-HSCT (2 months vs. 99 months, P<0.001). Treatment regimens were heterogeneous, with reduction of immunosuppression in combination with rituximab being the most common first-line treatment strategy in both cohorts (allo-HSCT: 66%; SOT: 80%). The overall response rate was lower in the allo-HSCT (67%) as compared to the SOT group (100%). Consequently, the overall survival (OS) trended towards a worse outcome for the allo-HSCT group (1-year OS: 54% vs. 78%; P=0.58). We identified PTLD onset ≤150 days in the allo-HSCT (P=0.046) and ECOG >2 in the SOT group (P=0.03) as prognostic factors for lower OS., Conclusion: PTLD cases present heterogeneously and pose unique challenges after both types of allogeneic transplantation., Competing Interests: UH received consulting fees or honoraria from Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lückemeier, Radujkovic, Holtick, Kurch, Monecke, Platzbecker, Herling and Kayser.)
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- 2023
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35. CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany.
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Bader P, Rossig C, Hutter M, Ayuk FA, Baldus CD, Bücklein VL, Bonig H, Cario G, Einsele H, Holtick U, Koenecke C, Bakhtiar S, Künkele A, Meisel R, Müller F, Müller I, Penack O, Rettinger E, Sauer MG, Schlegel PG, Soerensen J, von Stackelberg A, Strahm B, Hauer J, Feuchtinger T, and Jarisch A
- Subjects
- Adolescent, Young Adult, Humans, Child, Retrospective Studies, Immunotherapy, Adoptive, Recurrence, T-Lymphocytes, Hematopoietic Stem Cell Transplantation adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Patients with precursor B-cell acute lymphoblastic leukemia (pB-ALL) who have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), have relapsed more than once, or are resistant upfront have a dismal prognosis. CD19-targeted chimeric antigen receptor (CAR) T cells have evolved as potent immune therapies. Tisagenlecleucel (Tisa-cel) is a commercially available autologous CD19-directed CAR T-cell product. We performed a retrospective study inviting all CAR T-cell centers in Germany to participate. Eighty-one patients with pB-ALL were included. Twenty-eight days after CAR T-cell infusion, 71 patients (87.7%) were in complete response, and 8 (9.9%) were in nonremission. At 2 years, the probabilities of event-free survival (pEFS), relapse-free survival (pRFS), and overall survival (pOS) were 45.3%, 51.7%, and 53.2%, respectively. pEFS was not different in patients without (n = 16, 55.0%) vs with prior allo-HSCT (n = 65, 43.4%). In patients treated after allo-HSCT, the time to relapse after allo-HSCT was a strong predictor of outcome. Patients relapsing within 6 months of allo-HSCT had a disappointing pEFS of 18.4% (pOS = 16.0%); the pEFS for those relapsing later was 55.5% (pOS = 74.8%). Our study provides real-world experience in pediatric, adolescent, and young adult patients with ALL treated with Tisa-cel, where most patients were treated after having relapsed after allo-HSCT. A total of 45.3% were rescued with a single dose of Tisa-cel. Our novel finding that patients with ALL after allo-HSCT had by far a better pEFS if relapse occurred beyond 6 months might be helpful in clinical decision-making and motivates studies to uncover the reasons., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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36. CMV-IgG pre-allogeneic hematopoietic stem cell transplantation and the risk for CMV reactivation and mortality.
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Eberhardt KA, Jung V, Knops E, Heger E, Wirtz M, Steger G, Kaiser R, Affeldt P, Holtick U, Klein F, Scheid C, and Di Cristanziano V
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- Humans, Retrospective Studies, Transplantation, Homologous adverse effects, Cytomegalovirus physiology, Antibodies, Viral, Immunoglobulin G, Cytomegalovirus Infections, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Cytomegalovirus (CMV) represents one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, a common diagnostic test used to stratify the risk for CMV infection in allo-HSCT recipients is the qualitative CMV serology of donor and recipient. A positive serostatus of the recipient is the most important risk factor for CMV reactivation and associated with reduced overall survival post-transplantation (TX). Direct and indirect effects of CMV are involved in the poorer survival outcome. The present study investigated if the quantitative interpretation of anti-CMV IgG before allo-HSCT might serve as a novel parameter for the identification of patients at risk for CMV reactivation and worse outcome post-TX. For this purpose, a cohort of 440 allo-HSCT recipients over a period of 10 years was retrospectively analyzed. Our findings indicated that patients with high CMV IgG pre-allo-HSCT had a higher risk to develop CMV reactivation, including clinically relevant infections, and a worse prognosis 36 months post-allo-HSCT as compared to recipients with low CMV IgG values. In the letermovir (LMV) era, this group of patients might benefit from a closer CMV monitoring, and hence, earlier intervention if needed, especially after discontinuation of prophylaxis., (© 2023. The Author(s).)
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- 2023
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37. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.
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Crees ZD, Rettig MP, Jayasinghe RG, Stockerl-Goldstein K, Larson SM, Arpad I, Milone GA, Martino M, Stiff P, Sborov D, Pereira D, Micallef I, Moreno-Jiménez G, Mikala G, Coronel MLP, Holtick U, Hiemenz J, Qazilbash MH, Hardy N, Latif T, García-Cadenas I, Vainstein-Haras A, Sorani E, Gliko-Kabir I, Goldstein I, Ickowicz D, Shemesh-Darvish L, Kadosh S, Gao F, Schroeder MA, Vij R, and DiPersio JF
- Subjects
- Adult, Humans, Transplantation, Autologous, Prospective Studies, Hematopoietic Stem Cell Mobilization methods, Hematopoietic Stem Cells metabolism, Antigens, CD34 metabolism, Granulocyte Colony-Stimulating Factor pharmacology, Granulocyte Colony-Stimulating Factor therapeutic use, Immunologic Factors therapeutic use, Multiple Myeloma drug therapy, Heterocyclic Compounds pharmacology, Heterocyclic Compounds therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34
+ hematopoietic stem and progenitor cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 106 CD34+ cells kg-1 within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34+ HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529., (© 2023. The Author(s).)- Published
- 2023
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38. LONG-TERM FOLLOW-UP OF ASYMMETRIC BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION IN A PATIENT WITH METASTASIZED UROTHELIAL CARCINOMA.
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Lentzsch AM, Siggel R, Schnorr C, Holtick U, and Liakopoulos S
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- Female, Humans, Middle Aged, Follow-Up Studies, Endothelial Growth Factors, Tomography, Optical Coherence, Cell Proliferation, Fluorescein Angiography, Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Retinal Neoplasms, Cataract
- Abstract
Purpose: To report a case of bilateral diffuse uveal melanocytic proliferation over 30 months follow-up., Methods: Multimodal imaging including ultra-wide-field color fundus photography, blue light fundus autofluorescence, swept-source optical coherence tomography, fluorescein angiography, and indocyanine green angiography., Results: A 49-year-old woman presented with decreased vision 2 months after bladder cancer surgery. Exudative retinal detachment and leopard spot pattern chorioretinopathy were observed in the right eye. Chemotherapy and cystectomy were initiated. Progressive bilateral vision loss occurred with melanocytic proliferation, choroidal thickening, subretinal fibrosis, fluid extravasation, rapid development of mature cataract, multiple iris cysts, and rubeosis, despite plasmapheresis and IV immunoglobulins. After cataract surgery, massive fibrin reaction resulted in a ciliolenticular block. One year later, positron emission tomography-computed tomography revealed absence of metastases. At Month 23, choroidal thickness increased in line with tumor progression. Palliative systemic therapy was initiated. Secondary macular neovascularization was treated with intravitreal antivascular endothelial growth factor injections. Visual acuity was light perception in the right eye and 20/200 in the left eye at last follow-up., Conclusion: Bilateral diffuse uveal melanocytic proliferation results in progressive melanocyte proliferation and exudation, leading to severe visual loss. In our case, visual acuity was preserved at a low level in one eye under continuous systemic treatment. Systemic corticosteroids are recommended for cataract surgery in the setting of bilateral diffuse uveal melanocytic proliferation to prevent massive fibrin reaction. Intravitreal antivascular endothelial growth factor injections may be indicated if secondary macular neovascularization develops.
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- 2023
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39. Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study.
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Gagelmann N, Wulf GG, Duell J, Glass B, van Heteren P, von Tresckow B, Fischer M, Penack O, Ayuk F, Einsele H, Holtick U, Thomson J, Dreger P, and Kröger N
- Subjects
- Humans, Leukocyte Count, Neutrophils, Hematopoietic Stem Cells, Immunotherapy, Adoptive methods, Neutropenia
- Abstract
Hematotoxicity after chimeric antigen receptor (CAR) T-cell therapy is associated with infection and death but management remains unclear. We report results of 31 patients receiving hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic) for either sustained severe neutropenia of grade 4 (<0.5 × 109/L), sustained moderate neutropenia (≤1.5 × 109/L) and high risk of infection, or neutrophil count ≤2.0 × 109/L and active infection. Median time from CAR T-cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia before HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia (P = .007). All nonresponders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia (≤38 days; 85%) vs neutropenia >38 days before HSCB (44%; P = .029). In conclusion, early or prophylactic HSCB showed quick response and improved outcomes for sustained moderate to severe neutropenia after CAR-T., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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40. Impact of age on outcome of CAR-T cell therapies for large B-cell lymphoma: the GLA/DRST experience.
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Dreger P, Holtick U, Subklewe M, von Tresckow B, Ayuk F, Wagner E, Wulf G, Marks R, Penack O, Schnetzke U, Koenecke C, von Bonin M, Stelljes M, Glass B, Baldus CD, Vucinic V, Mougiakakos D, Topp M, Schroers R, Wolff D, Thomas S, Kröger N, and Bethge WA
- Subjects
- Humans, T-Lymphocytes, Antigens, CD19, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse therapy
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- 2023
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41. Mocravimod, a Selective Sphingosine-1-Phosphate Receptor Modulator, in Allogeneic Hematopoietic Stem Cell Transplantation for Malignancy.
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Dertschnig S, Gergely P, Finke J, Schanz U, Holler E, Holtick U, Socié G, Medinger M, Passweg J, Teshima T, Stylianou C, Oehen S, Heim D, and Bucher C
- Subjects
- Humans, Graft vs Host Disease prevention & control, Leukemia, Myeloid, Acute drug therapy, Methotrexate therapeutic use, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Immunosuppressive Agents adverse effects, Sphingosine-1-Phosphate Receptors antagonists & inhibitors
- Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the sole curative option for patients with acute myelogenous leukemia. Outcomes are limited by leukemia relapse, graft-versus-host disease (GVHD), and abnormal immune reconstitution. Mocravimod (KRP203) is an oral sphingosine-1-phosphate receptor (S1PR) modulator that blocks the signal required by T cells to egress from lymph nodes and other lymphoid organs. Mocravimod retains T cell effector function, a main differentiator to immunosuppressants. In preclinical models, mocravimod improves survival by maintaining graft-versus-leukemia (GVL) activity while reducing GVHD. In patients undergoing allo-HSCT for hematological malignancies, mocravimod is postulated to prevent GVHD by redistributing allogeneic donor T cells to lymphoid tissues while allowing a sufficient GVL effect in the lymphoid, where malignant cells usually reside. The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimod-phosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single- and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials.gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT. Mocravimod resulted in a significant reduction of circulating lymphocyte numbers and had no negative impact on engraftment and transplantation outcomes. Our results indicate that mocravimod is safe and support a larger study to investigate its efficacy in a homogeneous acute myelogenous leukemia patient population undergoing allo-HSCT., Competing Interests: Declaration of Competing Interest S.D. is an employee of Priothera SAS. P.G. is an employee of Novartis. S.O. was an employee of Novartis and is currently an employee of Priothera SAS., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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42. Characteristics and outcomes of patients undergoing high-dose chemotherapy and autologous stem cell transplantation admitted to the intensive care unit: a single-center retrospective analysis.
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Garcia Borrega J, Böll B, Kochanek M, Naendrup JH, Simon F, Sieg N, Hallek M, Borchmann P, Holtick U, Shimabukuro-Vornhagen A, Eichenauer DA, and Heger JM
- Subjects
- Humans, Female, Middle Aged, Male, Retrospective Studies, Transplantation, Autologous, Hospitalization, Intensive Care Units, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Stem Cell Transplantation, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
High-dose chemotherapy and autologous stem cell transplantation (ASCT) can be associated with adverse events necessitating treatment on the intensive care unit (ICU). Data focusing on patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT are scarce. We thus conducted a single-center retrospective analysis comprising 79 individuals who had high-dose chemotherapy and ASCT between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after ASCT. The median age was 57 years (range: 20-82 years); 38% of patients were female. B-cell non-Hodgkin lymphoma (34%) and plasma cell disorders (28%) were the most common indications for high-dose chemotherapy and ASCT. Sepsis represented the major cause for ICU admission (68%). Twenty-nine percent of patients required mechanical ventilation (MV), 5% had renal replacement therapy, and 44% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 77.2%, 77.2%, 72.2%, and 60.3%, respectively. Stable disease or disease progression prior to the initiation of high-dose chemotherapy (p = 0.0028) and MV (p < 0.0001) were associated with an impaired survival. A total of 36 patients died during observation. The most frequent causes of death were the underlying malignancy (44%) and sepsis (39%). Taken together, the present analysis indicates a favorable overall outcome for patients admitted to the ICU during hospitalization for high-dose chemotherapy and ASCT. Thus, this patient group should not be denied admission and treatment on the ICU., (© 2022. The Author(s).)
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- 2023
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43. Health Economic Aspects of Platelet Concentrates: Comparing Cost and Reimbursement of Pathogen Inactivated and Conventional Platelet Concentrates in a German Comprehensive Cancer Center.
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Bonn J, Baltin CT, Osterkamp V, Scheid C, Holtick U, Irsch J, and Kron F
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- Humans, Retrospective Studies, Hospitalization, Intensive Care Units, Hospitals, University, Diagnosis-Related Groups, Neoplasms
- Abstract
Introduction: Pathogen inactivation (PI) utilizing amotosalen and UVA light (INTERCEPT® Blood System) is a well-established method for the production of safer platelet concentrates (PCs). While many studies describe clinical and logistical benefits of PI, the implications and potential challenges from a hospital management perspective have not yet been analyzed - health economic analyses considering reimbursement of PI are lacking. The objective of this analysis was to examine the real-life inpatient treatment costs from a hospital perspective and to assess the economic impact of PI-PC versus conventional PC (CONV-PC) administration in Germany., Methods: Real-life cost data for inpatient cancer cases from 2020 of the University Hospital Cologne were identified by operating and procedure codes. The German diagnosis-related groups, extra fees, case mix index (CMI), length of stay (LOS), and average resource consumption of PC were evaluated from a micro-management perspective. The potential economic impact of implementing PI-treated PCs was modeled retrospectively., Results: In total, 951 inpatient cases were analyzed (CMI [median 4.7-9.9], LOS [median 26 days], number of cases in intensive care units [38%]). The median DRG fee was between EUR 13,800 and EUR 26,400. According to our model, the use of PI-PC compared to CONV-PC would result in savings between EUR 184 and EUR 306 per case., Conclusion: From a hospital management perspective, oncological cases requiring PC transfusion are associated with a high CMI (reimbursement per DRG flat fee) and moderate costs with sufficient add-on payment for PI on a case level. Investment and process costs for PI implementation can be analyzed for site-specific scenarios., (S. Karger AG, Basel.)
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- 2023
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44. Desiccating Stress Significantly Increases the Risk for Chronic Ocular Graft-versus-Host-Disease.
- Author
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Gehlsen U, Stern ME, Franklin J, Tahmaz V, Hallek M, Holtick U, Scheid C, and Steven P
- Subjects
- Humans, Retrospective Studies, Transplantation, Homologous adverse effects, Graft vs Host Disease epidemiology, Hematopoietic Stem Cell Transplantation adverse effects, Dry Eye Syndromes epidemiology
- Abstract
Desiccating stress (DS) is known to induce dry eye disease but has not been studied in the context of ocular graft-versus-host disease (oGVHD). Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are exposed to DS on transplantation wards, which are highly climate-regulated for hygienic purposes. Because oGVHD demonstrates features of dry eye disease, this retrospective study aimed to analyze DS as a risk factor for chronic oGVHD. A total of 444 patients undergoing allo-HSCT were investigated with a maximum follow-up of 5.8 years post-transplantation. Relative humidity (%rH) on the transplantation ward was monitored, and data were correlated with the occurrence, severity, and onset of chronic oGVHD, as well as the occurrence of acute skin GVHD. A logistic regression model was used to predict the development of oGVHD. One hundred three of 213 surviving patients developed oGVHD. oGVHD was significantly correlated with a lower %rH (r = .2; P = .03), and more patients (73%) developed oGVHD after transplantation under DS compared with patients after transplantation under high-humidity conditions (30%; P = .02). Reduced humidity increased the relative risk for oGVHD by 4% for each %rH, but it did not affect the severity or time of first diagnosis of oGVHD. In this study, we demonstrate that DS is an independent risk factor for oGVHD. Adjusting air humidity during allo-HSCT has the potential to serve as a preventive measure with clinical relevance., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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45. Clinical exercise therapy program with multiple myeloma patients: Impacts on feasibility, adherence and efficacy.
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Wefelnberg MM, Niels T, Holtick U, Jundt F, Scheid C, and Baumann FT
- Subjects
- Humans, Feasibility Studies, Exercise Therapy adverse effects, Exercise, Surveys and Questionnaires, Multiple Myeloma therapy
- Abstract
Purpose: Multiple myeloma (MM) is a severe hemato-oncological disease with high mortality and increasing incidence rate. Since evidence on exercise therapy in MM patients remains limited, this study examines feasibility, adherence, and efficacy based on real-life data from an oncologic care structure., Methods: A data evaluation of MM patients who participated in the oncologic exercise and movement therapy (OTT) at the Cologne University Hospital between 2012 and 2019 was conducted. The patient flow was incrementally reduced to four cohorts, intention-to-treat cohort (ITTC), safety cohort (SC), adherence cohort (AC), and efficacy cohort (EC). Cohorts were evaluated descriptively and by means of correlation analysis as well as group and time comparisons., Results: Thirty patients registered at the OTT between 2012 and 2019 (ITTC). The SC (N = 26) attended exercise therapy on average about one session per week over a period of 8 months. One-third dropped out within 3 months. In the AC (N = 15), BMI at baseline exhibited a strong and very significant negative correlation with exercise adherence. In the EC (N = 8), a significant improvement in physical functioning and a tendency towards significance in fatigue reduction between two measurement points was observed. No adverse events were documented., Conclusions: The present observatory study reveals safety and feasibility while indicating adherence and efficacy of exercising MM patients under real-life therapy circumstances. Found obstacles to exercising as well as improvements in questionnaire scale scores need to be further examined in confirmatory study designs., (© 2022. The Author(s).)
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- 2022
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46. GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany.
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Bethge WA, Martus P, Schmitt M, Holtick U, Subklewe M, von Tresckow B, Ayuk F, Wagner-Drouet EM, Wulf GG, Marks R, Penack O, Schnetzke U, Koenecke C, von Bonin M, Stelljes M, Glass B, Baldus CD, Vucinic V, Mougiakakos D, Topp M, Fante MA, Schroers R, Bayir L, Borchmann P, Buecklein V, Hasenkamp J, Hanoun C, Thomas S, Beelen DW, Lengerke C, Kroeger N, and Dreger P
- Subjects
- Antigens, CD19, Germany epidemiology, Humans, Immunotherapy, Adoptive adverse effects, Lymphoma, Large B-Cell, Diffuse pathology, Neutropenia chemically induced
- Abstract
CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies., (© 2022 by The American Society of Hematology.)
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- 2022
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47. Salvage High-dose Melphalan With Autologous Stem cell Transplantation as Bridge to Consolidation Therapy for Chemoresistant Aggressive B-cell Lymphoma.
- Author
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Kaddu-Mulindwa D, Gödel P, Kutsch N, Heger JM, Scheid C, Borchmann P, Holtick U, Held G, Thurner L, Bewarder M, Rixecker T, and Bittenbring JT
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Consolidation Chemotherapy, Humans, Melphalan therapeutic use, Neoplasm Recurrence, Local drug therapy, Retrospective Studies, Salvage Therapy methods, Stem Cell Transplantation, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation methods, Lymphoma drug therapy, Lymphoma, B-Cell drug therapy
- Abstract
Background: Patients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities., Materials and Methods: In this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy., Results: We identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non-relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy., Conclusion: Single agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy., Microabstract: Patient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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48. Sustained Remission of Relapsed Diffuse Large B-cell Lymphoma After Safe Administration of CD19-directed CAR T-cells in a Patient With Chronic Intestinal and Pulmonal GvHD.
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Kutsch N, Gödel P, Voltin CA, Kobe C, Hallek M, Scheid C, Borchmann P, and Holtick U
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- 2022
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49. High Mortality of COVID-19 Early after Allogeneic Stem Cell Transplantation: A Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group.
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Schaffrath J, Brummer C, Wolff D, Holtick U, Kröger N, Bornhäuser M, Kraus S, Hilgendorf I, Blau IW, Penack O, Wittke C, Steiner N, Nachbaur D, Thurner L, Hindahl H, Zeiser R, Maier CP, Bethge W, and Müller LP
- Subjects
- Adult, Aged, Aged, 80 and over, Humans, Middle Aged, Pandemics, Retrospective Studies, SARS-CoV-2, Young Adult, COVID-19 epidemiology, Hematopoietic Stem Cell Transplantation
- Abstract
Recipients of allogeneic stem cell transplantation (alloSCT) are at high risk for contracting infectious diseases with high morbidity and mortality. Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that can lead to severe pneumonia and acute respiratory distress syndrome, with a potentially fatal outcome. In this retrospective study conducted on behalf of the German Cooperative Transplant Study Group, we aimed to analyze risk factors, disease course, and outcomes of COVID-19 in patients who underwent alloSCT. AlloSCT recipients who became infected with SARS-CoV-2 at German and Austrian transplant centers between February 2020 and July 2021 were included. Classification of COVID-19 severity into mild, moderate-severe, or critical disease and division of the course of the pandemic into 4 phases were done according to the German Robert Koch Institute. The main endpoint was overall mortality at the end of follow-up. We further analyzed the need for treatment in an intensive care unit (ICU) and the severity of disease. Risk factors were evaluated using univariate and multivariate analyses, and survival analysis was performed using Kaplan-Meier method. The study cohort comprised 130 patients from 14 transplant centers, with a median age at diagnosis of COVID-19 of 59 years (range, 20 to 81 years) and a median interval between alloSCT and COVID-19 of 787 days (range, 19 to 8138 days). The most common underlying diseases were acute myeloid leukemia (45.4%) and lymphoma (10.8%). The majority of patients (84.9%) were infected in the later phases of the pandemic; 20.8% had moderate-severe disease, 12.3% had critical disease, and 19.2% were treated in an ICU. After a median follow-up of 127 days, overall mortality was 16.2%, 52.0% among patients treated in an ICU. Risk factors for mortality in multivariate analysis were active disease (odds ratio [OR], 4.46), infection with SARS-CoV-2 ≤365 days after alloSCT (OR, 5.60), age >60 years (OR, 5.39), and ongoing immunosuppression with cyclosporine (OR, 8.55). Risk factors for developing moderate-severe or critical disease were concurrent immunosuppression (OR, 4.06) and age >40 years (OR, 4.08). Patients after alloSCT exhibit a substantially increased mortality risk after COVID-19 infection compared with the normal population, without considerable improvement over the course of the pandemic. Risk factors include age, early infection post-alloSCT, and active immunosuppression. Further studies are needed to improve prevention and treatment in this high-risk patient group., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2022
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50. Allogeneic stem cell transplant recipients admitted to the intensive care unit during the peri-transplant period have unfavorable outcomes-results of a retrospective analysis from a German university hospital.
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Garcia Borrega J, Heger JM, Koehler P, Holtick U, Hallek M, Scheid C, Böll B, Shimabukuro-Vornhagen A, Kochanek M, and Eichenauer DA
- Subjects
- Adult, Aged, Female, Germany, Hematopoietic Stem Cell Transplantation adverse effects, Hospitalization, Hospitals, University, Humans, Intensive Care Units, Male, Middle Aged, Respiration, Artificial, Retrospective Studies, Transplantation Conditioning adverse effects, Transplantation, Homologous adverse effects, Treatment Outcome, Young Adult, Stem Cell Transplantation adverse effects
- Abstract
The prognosis of allogeneic stem cell transplant recipients admitted to the intensive care unit (ICU) has improved over the last decades. However, data focusing on patients treated in the ICU during the peri-transplant period are scarce. We therefore conducted an analysis comprising 70 patients who had allogeneic stem cell transplantation at the University Hospital Cologne between 2014 and 2020 and were admitted to the ICU between the initiation of conditioning therapy and day 30 after transplantation. The median age was 59 years (range: 18 - 72 years). 50% of patients were female. Sepsis was the most common cause for ICU admission (49%). Mechanical ventilation (MV) was required in 56% of patients, 27% had renal replacement therapy (RRT), and 64% needed vasopressors. The ICU, hospital, 90-day, and 1-year survival rates were 48.6%, 38.6%, 35.7%, and 16.2%, respectively. MV and/or RRT during the ICU stay were associated with an impaired survival (p < 0.0001). The same was true for the use of vasopressors (p < 0.0001). In contrast, baseline characteristics did not impact the outcome. Cardiopulmonary resuscitation (CPR) was performed in 17% of patients. None of the patients undergoing CPR was alive at 1 year. Among patients who died after discharge from the ICU (n = 23), sepsis and other infectious complications represented the major causes of death (48%). Taken together, the present analysis indicates unfavorable outcomes for allogeneic stem cell transplant recipients admitted to the ICU during the peri-transplant period. The data may help to make informed decisions with patients and their families., (© 2021. The Author(s).)
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- 2022
- Full Text
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