Kooperativer Bibliotheksverbund

In: Nature Neuroscience, Springer Science and Business Media LLC, Vol. 26, No. 4 ( 2023-04), p. 673-681

Type of Medium: Online Resource

ISSN: 1097-6256 , 1546-1726

URL: Article

DOI: 10.1038/s41593-023-01286-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1494955-6

SSG: 12

In: Nature Neuroscience, Springer Science and Business Media LLC, Vol. 26, No. 6 ( 2023-06), p. 1127-1128

Type of Medium: Online Resource

ISSN: 1097-6256 , 1546-1726

URL: Article

DOI: 10.1038/s41593-023-01328-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1494955-6

SSG: 12

In: American Journal of Hematology, Wiley, Vol. 96, No. 6 ( 2021-06)

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v96.6

DOI: 10.1002/ajh.26162

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4360-4360

Abstract: Background: PPM1D is a serine/threonine phosphatase that inactivates p53 tumor suppressor pathway. Recently, PPM1D mutations have been described in clonal hematopoiesis and are more frequently found in therapy-related MDS than in primary MDS (15% vs. 3%). Del(5q), is the most prevalent cytogenetic abnormality in MDS. A high proportion of MDS del(5q) patients respond to lenalidomide, but almost 40% of them progress to AML. Scharenberg et al. identified recurrent mutations in a limited number of genes i.e. TP53, RUNX1, and TET2 in a longitudinal cohort of 35 MDS del(5q) patients that progressed to AML. The clinical impact and occurrence of PPM1D mutations in MDS del(5q) patients remains unknown. Aim: To determine the clinical impact of PPM1D mutations in MDS del (5q) patients on lenalidomide resistance and AML progression. Methods: We studied a cohort of 243 patients with MDS or AML following MDS and 5q deletion diagnosed according to the 2008 WHO classification. Patients were cytogenetically characterized by chromosome banding analysis and followed for disease progression, treatment and survival. From 22 del(5q) patients treated with lenalidomide, follow-up (FU) material was available before and after treatment. Molecular analysis for mutations in all 6 exons of PPM1D was performed by Sanger and/or a next-generation sequencing panel covering mutations in 46 genes frequently mutated in MDS, including TP53 and CSNK1A1. Results: At the time of diagnosis 14 PPM1D mutations were detected in 13 of 243 (5.3%) MDS patients with del(5q), 12 of which were found in the previously described hotspot region of PPM1D between amino acids 427 and 542. Six patients had nonsense mutations, 3 patients had frameshift mutations (one patient with 2 frameshift mutations), and 4 patients had missense mutations. TP53 mutations were found in 34 of 243 (14%) MDS patients with del(5q). Three TP53 mutated patients, two with complex karyotype, carried an additional PPM1D mutation. Co-occurrence of PPM1D and CSNK1A1 mutations was not observed in any patient. In total, 71 of 243 patients were treated with lenalidomide and had available information about treatment response. Eleven patients (15.5%) did not respond to lenalidomide and 17 patients (24%) progressed to AML. Nine of 71 (12.6%) patients were TP53 (n=5, 7%) or PPM1D mutated (n=4, 5.6%). For 22 of 71 patients who either achieved a complete remission (n=5), developed resistance to lenalidomide followed by MDS progression (n=7) or AML transformation (n=10), FU samples were available before and after lenalidomide treatment. Of the 5 patients with complete remission 4 patients displayed no mutations, while 1 patient was PPM1D- and ASXL1-mutated with a variant allele frequency (VAF) of 27.6% and 12.1%, respectively, prior to lenalidomide treatment. After 76 months on lenalidomide, both mutations had disappeared. Of the 17 patients with lenalidomide resistance/AML progression, 5 patients (29.4%) carried mutations either in PPM1D (n=2) or in TP53 (n=3) prior to lenalidomide treatment, with a mean VAF of 15.3% and 13.5%, respectively. The 2 PPM1D-mutated patients progressed to AML 59.4 and 79.6 months after diagnosis. None of the 3 initially TP53-mutated patients progressed to AML. All 3 TP53-mutated patients co-expressed SF3B1 mutations. At the time of lenalidomide resistance/AML progression, we observed 2 known and 1 novel PPM1D mutation in a patient previously wildtype for PPM1D and TP53, 3 known and 6 novel TP53 mutations in 5 patients previously wildtype for PPM1D and TP53, and 1 novel TP53 mutation in a patient who was previously found mutated in PPM1D. Thus, at the time of lenalidomide resistance or AML progression 10 of 17 patients (58.8%) were mutated for PPM1D (n=3, 18%) and/or TP53 (n=9, 53%; 2 of 9 co-expressed PPM1D mutations). At the time of lenalidomide resistance/AML progression, VAF increased from 10.2% to 23.3% for PPM1D and from 4% to 16.9% for TP53 mutations, indicating expansion of the mutated clone under the selective pressure of lenalidomide. Conclusion: PPM1D mutations are recurrently found in MDS del(5q) patients at a frequency of 5.3% and may be coexpressed with TP53 mutations in 5q- MDS/AML cells. Frequency at resistance/AML progression was 18% for PPM1D and 53% for TP53 mutated patients, respectively. Our findings indicate an association of PPM1D mutations in addition to the previously described TP53 mutations with lenalidomide resistance and AML progression. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Krönke:Celgene: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Koenecke:Amgen: Consultancy; Roche: Consultancy; abbvie: Consultancy; BMS: Consultancy. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Valent:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Platzbecker:Celgene: Research Funding. Heuser:BergenBio: Research Funding; StemLine Therapeutics: Consultancy; Astellas: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer Pharma AG: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-114026

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 912-912

Abstract: Introduction: The landscape of molecular aberrations in patients with myelodysplastic syndromes (MDS) has been well characterized and has identified ASXL1, BCOR, CUX1, IDH1, IDH2, SRSF2, RUNX1, U2AF1, TP53 and others as negative prognostic markers for overall survival (OS). We comprehensively investigated the prognostic impact of genetic aberrations in the context of allogeneic hematopoietic stem cell transplantation (alloHSCT) in a large cohort of patients with high risk MDS or secondary AML following MDS (sAML). Patients and Methods: 308 Patients with a diagnosis of MDS (47.4%) or sAML (52.6%) who received an alloHSCT at four German university medical centers and for whom genomic DNA was available at a time with active disease before transplantation were evaluated for the presence of mutations in 54 genes by Illumina high-throughput sequencing. Results: At least one mutation was identified in 82% of our patients with a median number of 2 mutations per patient. The most frequently mutated genes were ASXL1 (24.4%), DNMT3A, (23.1%), RUNX1 (16.9%), TET2 (16.9%), STAG2 (12%), TP53 (11.7%), and SRSF2 (11%) in agreement with previous reports. Mutation frequencies were similar between MDS and sAML patients for all mutated genes except SRSF2, TET2 and WT1, which were more frequently mutated in sAML. We grouped the mutated genes into functional classes and found that patients most frequently had mutations in modifiers of DNA methylation (42.2%), followed by chromatin modifiers (41.5%), splicing genes (31.1%), transcription factors (30.8%), signal transducers (28.8%) and tumor suppressors (14.6%). Mean variant allele frequencies were highest in modifiers of DNA methylation (33.2%), while signal transducers had the lowest allele frequency (20.4%). We next assessed the prognostic impact of gene classes and individual genes on outcome of patients after alloHSCT. Median follow up from transplantation was 4.15 years. Median patient age at time of HSCT was 58 years (range 19-75). 76 patients (25%) werein complete remission and 232 patients (75%) had active disease before transplantation. Low, intermediate, and high risk cytogenetics according to IPSS were found in 116 (38%), 59 (19%), and 115 (37%) patients, respectively. Matched and mismatched related donor HSCT was performed in 71 and 4 patients, respectively (23.1 and 1.3%), and matched and mismatched unrelated donor HSCT in 171 and 62 patients, respectively (55.5 and 20.1%). The six functional gene classes had no prognostic impact on survival, cumulative incidence of relapse and non-relapse mortality. We therefore evaluated the prognostic impact of individual gene mutations, of aberrations of chromosomes 3, 5, 7, 8, 17, 20 or a complex karyotype, and of transplant characteristics on OS. Parameters with significant impact on OS in univariate analysis were included in a multivariate cox proportional hazards model. Significant predictors of OS in multivariate analysis were mutations in PTPN11 (HR 3.1, present in 2.3% of pts.), IDH2 (HR 2.6, present in 4.2%), PHF6 (HR 2.2, present in 4.9%), NRAS (HR 1.8, present in 7.5%), presence of a complex karyotype (HR 1.8, present in 16.6%), transplantation from haploidentical donor (HR 5.5), RAEB/sAML not in complete remission before transplantation compared to untreated RA/RARS or RAEB/sAML and treated RAEB/sAML in remission (HR 2.0), GvHD prophylaxis other than calcineurin inhibitor with methotrexate or mycophenolate mofetil (HR 1.7) and female sex of the donor (HR 1.7). TP53 mutations lost their unfavorable prognostic impact when complex karyotype was added to the multivariate model. Competing risk analysis for cumulative incidence of relapse and non-relapse mortality showed that IDH2 and NRAS mutations and a complex karyotype were significantly associated with higher risk for relapse while PTPN11 and PHF6 mutations predicted for a higher incidence of non-relapse mortality. Importantly, a negative prognostic impact of ASXL1, BCOR, CUX1, IDH1, SRSF2, RUNX1 and U2AF1 seen previously in MDS patients not undergoing alloHSCT was not found in the transplant setting, suggesting that alloHSCT may overcome the unfavorable effect of these mutations. Conclusion: By extensive genetic characterisation of 308 MDS or sAML patients undergoing alloHSCT we identified mutations in IDH2, NRAS and complex karyotype as predictors of relapse and reduced OS and provide a matrix to refine risk prediction for allogeneic HSCT. Disclosures Heuser: Karyopharm: Research Funding. Platzbecker:Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.912.912

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3555-3555

Abstract: Background: The PTLD-1 trials established 1 st-line risk-stratified sequential treatment (RSST) of CD20-positive B-cell PTLD in adult solid organ transplant recipients. After rituximab induction, patients (pts) in complete remission (CR) continue with 4 three-weekly courses of rituximab, while all others receive 4 cycles of R-CHOP-21 (Trappe RU et al., JCO 2017;35:536-43). Analyses of the initial PTLD-1 sequential treatment cohort uniformly treated with rituximab followed by CHOP identified the prognostic value of response to rituximab induction, international prognostic index (IPI) risk factors (≥ 3 vs & lt; 3) and thoracic SOT (Trappe RU et al., Am J Transplant 2015;15:1091-100). The PTLD-2 trial therefore tested modified risk-stratification based on these three risk factors. The key hypothesis was that rituximab SC monotherapy consolidation in an expanded low-risk group would be superior to CHOP consolidation in comparable pts of the PTLD-1 trial by demonstrating an improved event-free survival (EFS) at 2 years, based on a lower rate of grade 3/4 infections and similar efficacy. Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrolled treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria were CNS involvement, ECOG & gt; 2, pregnancy, severe organ dysfunction or severe, active infection. Treatment consisted of rituximab SC on days (d) 1, 8, 15 and 22. After restaging on d50, pts in CR as well as those in partial remission with & lt; 3 IPI risk factors at diagnosis (low-risk group) continued with rituximab SC monotherapy. Most other pts (high-risk group) received 4 cycles of R SC-CHOP-21 chemotherapy, while thoracic SOT recipients who progressed under rituximab (very-high-risk group) received six cycles of alternating R SC-CHOP-21 and modified R SC-DHAOx. In case of progression before d50, subsequent treatment started immediately. The primary endpoint was EFS (event: infections grade 3/4 from d50 to d143, treatment discontinuation, progression, death) in the low-risk group. Secondary endpoints were response and overall response rate (ORR) by computed tomography at interim and final staging, overall survival (OS), time to progression (TTP), progression-free survival (PFS), response duration and treatment-related mortality (TRM) overall and by risk group. Results: 60 pts were recruited at 15 centers (2015 - 2020). 29/60 were kidney, 14 lung, 9 liver, 4 heart transplant recipients (4 others). Median age was 54 years. 58/60 PTLD were monomorphic and 23/60 EBV-associated. 26/58 pts (45%, 95% CI 33-58) responded at interim staging. 21 were allocated to the low-risk, 28 to the high-risk and 9 to the very-high-risk group. ORR at final staging was 45/48 (94 %, 95% CI 83-98). Grade 3/4 infections were reported in 25/59 pts who started treatment (42%, 95% CI 31-55). TRM occurred in 4/59 pts (7 %, 95 % CI 2-17). With a median follow-up of 2.8 years, the 2-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (60 pts) were 78 % (95% CI 65-90, median not reached) and 68 % (95% CI 55-80, median OS 5.1 years), and thus in the range reported in the PTLD-1 trials. The prognostic value of response to rituximab induction, IPI risk factors (≥ 3 vs & lt; 3) and thoracic SOT was confirmed. The primary endpoint, 2-year EFS in the low-risk group, was 66 % (95% CI 45-86). Events were 4 grade 3 infections (19 %) and 5 relapses (24 %). There was no significant difference to the prespecified comparator group from the PTLD-1 ST trial cohort (52 % [95% CI 32-72]). The 3-year KM estimate of OS in the low-risk group was 100 %. Intensified chemotherapy in the very-high-risk group did not improve outcomes (median OS 7.4 months [95% CI 2.2-12.7] ) compared to PTLD 1 RSST (10.1 months). Conclusions: Overall efficacy and safety outcomes of the trial were comparable to the PTLD-1 trial despite the enrollment of 23% lung transplant recipients, who historically have poor outcomes (Zimmermann H et al. Transplantation Journal 2013;96:e18-9). 32 % of patients were treated with rituximab monotherapy in the low-risk group. The primary endpoint (improved EFS in this group vs. historical control) was not met. However, the observed 100% 3-year OS estimate in this population is an excellent outcome. The trial confirmed the poor prognosis of thoracic SOT recipients with progressive disease after rituximab induction. Intensified chemotherapy did not improve this outcome. Disclosures Zimmermann: Roche Germany: Research Funding; Atara Biotherapeutics: Other: Travel support, Research Funding; Janssen: Other: Travel support. Koenecke: Novartis: Consultancy; Janssen: Consultancy; BMS/Celgene: Consultancy; Kite/Gilead: Consultancy; EUSA Pharm: Consultancy. Dreyling: Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau. Dührsen: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; CPT Cellex Patient Treatment: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hahn: BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria; MSD: Consultancy, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Other: Travel support. Hauser: Roche: Honoraria; Astellas: Honoraria, Other: Travel Support; Biotest: Honoraria, Other: Travel support; Hexal: Other: Travel support; Neovii: Other: Travel support; Novartis: Consultancy, Honoraria. Wolf: Novartis: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Heuser: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; BergenBio: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolremo: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Schmidt: Novartis: Consultancy, Honoraria, Other: Travel support; Kite/Gilead: Consultancy, Honoraria, Other: Travel support, Research Funding; Takeda: Consultancy, Other: Travel support; BMS: Consultancy, Other: Travel support; Janssen: Other: Travel support. Ritgen: MSD: Consultancy, Other: Travel support; Chugai: Consultancy; Abbvie: Consultancy, Other: Travel support, Research Funding; Roche: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support. Siebert: AstraZeneca: Speakers Bureau. Anagnostopoulos: BMS: Consultancy, Honoraria, Other: Travel support; MSD: Consultancy, Honoraria, Other: Travel support. Trappe: Atara Biotherapeutics: Consultancy, Other: Travel support, Research Funding; Celgene: Other: Travel support; Jansen: Other: Travel support; AbbVie: Other: Travel support; GSK: Other: Travel support; Roche: Other: Travel support. OffLabel Disclosure: Rituximab is FDA-approved for the treatment of adult patients with CD20-positive, B-cell NHL, but not explicitly for PTLD, particularly as single agent treatment in DLBCL-PTLD.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146823

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Pediatric Blood & Cancer, Wiley, Vol. 68, No. 10 ( 2021-10)

Type of Medium: Online Resource

ISSN: 1545-5009 , 1545-5017

URL: Issue

URL: Article

DOI: 10.1002/pbc.v68.10

DOI: 10.1002/pbc.29185

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 2130978-4

In: Metabolic Engineering, Elsevier BV, Vol. 8, No. 6 ( 2006-11), p. 587-602

Type of Medium: Online Resource

ISSN: 1096-7176

URL: Article

DOI: 10.1016/j.ymben.2006.05.007

Language: English

Publisher: Elsevier BV

Publication Date: 2006

detail.hit.zdb_id: 1471017-1

SSG: 12

In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 18 ( 2022-09-18), p. 10914-

Abstract: Donor lymphocyte infusion (DLI) can (re-)induce durable remission in relapsing patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). However, DLI harbors the risk of increased non-relapse mortality due to the co-occurrence of graft-versus-host disease (GVHD). GVHD onset may be caused or accompanied by changes in the clonal T-cell receptor (TCR) repertoire. To investigate this, we analyzed T cells in a cohort of 21 patients receiving DLI after alloHSCT. We performed deep T-cell receptor β (TRB) sequencing of sorted CD4+CD25+CD127low regulatory T cells (Treg cells) and CD4+ conventional T cells (Tcon cells) in order to track longitudinal changes in the TCR repertoire. GVHD following DLI was associated with less diverse but clonally expanded CD4+CD25+CD127low Treg and CD4+ Tcon TCR repertoires, while patients without GVHD exhibited healthy-like repertoire properties. Moreover, the diversification of the repertoires upon GVHD treatment was linked to steroid-sensitive GVHD, whereas decreased diversity was observed in steroid-refractory GVHD. Finally, the unbiased sample analysis revealed that the healthy-like attributes of the CD4+CD25+CD127low Treg TCR repertoire were associated with reduced GVHD incidence. In conclusion, CD4+CD25+CD127low Treg and CD4+ Tcon TRB repertoire dynamics may provide a helpful real-time tool to improve the diagnosis and monitoring of treatment in GVHD following DLI.

Type of Medium: Online Resource

ISSN: 1422-0067

URL: Article

DOI: 10.3390/ijms231810914

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2019364-6

SSG: 12

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 96, No. 8 ( 2017-8), p. 1361-1372

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-017-3027-5

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2017

detail.hit.zdb_id: 1458429-3