Kooperativer Bibliotheksverbund

In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 149, No. 10 ( 2024-03-05), p. 747-759

Abstract: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP 〈 135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT ( P =0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients ( P =0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was −3.0 mm Hg (95% CI, −5.7, −0.2; P =0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were −5.4 mm Hg (−6.8, −4.0; P 〈 0.001) and −5.2 mm Hg (−7.1, −3.3; P 〈 0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02649426 and NCT03614260.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/CIRCULATIONAHA.123.066941

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2024

detail.hit.zdb_id: 1466401-X

detail.hit.zdb_id: 80099-5

In: Journal of Hematology & Oncology, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2022-12)

Abstract: Extramedullary manifestations (EM) are rare in acute myeloid leukemia (AML) and their impact on clinical outcomes is controversially discussed. Methods We retrospectively analyzed a large multi-center cohort of 1583 newly diagnosed AML patients, of whom 225 (14.21%) had EM. Results AML patients with EM presented with significantly higher counts of white blood cells ( p   〈  0.0001), peripheral blood blasts ( p   〈  0.0001), bone marrow blasts ( p  = 0.019), and LDH ( p   〈  0.0001). Regarding molecular genetics, EM AML was associated with mutations of NPM1 (OR: 1.66, p   〈  0.001), FLT3 -ITD (OR: 1.72, p   〈  0.001) and PTPN11 (OR: 2.46, p   〈  0.001). With regard to clinical outcomes, EM AML patients were less likely to achieve complete remissions (OR: 0.62, p  = 0.004), and had a higher early death rate (OR: 2.23, p  = 0.003). Multivariable analysis revealed EM as an independent risk factor for reduced overall survival (hazard ratio [HR]: 1.43, p   〈  0.001), however, for patients who received allogeneic hematopoietic cell transplantation (HCT) survival did not differ. For patients bearing EM AML, multivariable analysis unveiled mutated TP53 and IKZF1 as independent risk factors for reduced event-free (HR: 4.45, p   〈  0.001, and HR: 2.05, p  = 0.044, respectively) and overall survival (HR: 2.48, p  = 0.026, and HR: 2.63, p  = 0.008, respectively). Conclusion Our analysis represents one of the largest cohorts of EM AML and establishes key molecular markers linked to EM, providing new evidence that EM is associated with adverse risk in AML and may warrant allogeneic HCT in eligible patients with EM.

Type of Medium: Online Resource

ISSN: 1756-8722

URL: Article

DOI: 10.1186/s13045-022-01267-7

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2429631-4

In: Leukemia, Springer Science and Business Media LLC, Vol. 37, No. 12 ( 2023-12), p. 2395-2403

Abstract: Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1 , GATA2 , KRAS , KIT , SF3B1 , and ETV6 , while alterations of NPM1 , TET2 , FLT3 -ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1 -mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation ( n  = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-023-02061-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 807030-1

detail.hit.zdb_id: 2008023-2

In: Blood Advances, American Society of Hematology, Vol. 5, No. 17 ( 2021-09-14), p. 3279-3289

Abstract: The tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) is an important regulator of RAS signaling and frequently affected by mutations in patients with acute myeloid leukemia (AML). Despite the relevance for leukemogenesis and as a potential therapeutic target, the prognostic role is controversial. To investigate the prognostic impact of PTPN11 mutations, we analyzed 1529 adult AML patients using next-generation sequencing. PTPN11 mutations were detected in 106 of 1529 (6.93%) patients (median VAF: 24%) in dominant (36%) and subclonal (64%) configuration. Patients with PTPN11 mutations were associated with concomitant mutations in NPM1 (63%), DNMT3A (37%), and NRAS (21%) and had a higher rate of European LeukemiaNet (ELN) favorable cytogenetics (57.8% vs 39.1%; P & lt; .001) and higher white blood cell counts (P = .007) compared with PTPN11 wild-type patients. In a multivariable analysis, PTPN11 mutations were independently associated with poor overall survival (hazard ratio [HR]: 1.75; P & lt; .001), relapse-free survival (HR: 1.52; P = .013), and a lower rate of complete remission (odds ratio: 0.46; P = .008). Importantly, the deleterious effect of PTPN11 mutations was confined predominantly to the ELN favorable-risk group and patients with subclonal PTPN11 mutations (HR: 2.28; P & lt; .001) but not found with dominant PTPN11 mutations (HR: 1.07; P = .775), presumably because of significant differences within the rate and spectrum of associated comutations. In conclusion, our data suggest an overall poor prognostic impact of PTPN11 mutations in AML, which is significantly modified by the underlying cytogenetics and the clonal context in which they occur.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2021004631

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 2876449-3

detail.hit.zdb_id: 2915908-8

In: HemaSphere, Wiley, Vol. 7, No. S3 ( 2023-08), p. e72156a7-

Type of Medium: Online Resource

ISSN: 2572-9241

URL: Article

DOI: 10.1097/01.HS9.0000967464.72156.a7

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 2922183-3

In: Annals of Hematology, Springer Science and Business Media LLC, Vol. 102, No. 3 ( 2023-03), p. 547-561

Abstract: A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA ( n  = 132) or to the study group arms ( n  = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60–87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45–64)) and the study group arms (53% (95%CI: 47–60) and 59% (95%CI: 58–63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7–14.0) in the CSA, 7.6% (95%CI: 4.5–12.8) in study group A and 11.1% (95%CI: 9.0–13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0–26.9), 17.0% (95%CI: 2.0–23.9), and 19.5% (95%CI: 16.7–22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Type of Medium: Online Resource

ISSN: 0939-5555 , 1432-0584

URL: Article

DOI: 10.1007/s00277-023-05087-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 1064950-5

detail.hit.zdb_id: 1458429-3

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1066-1066

Abstract: Despite recent advances, treatment of elderly patients with AML remains a challenge because of adverse disease biology, comorbidities and therapy related toxicities. The balance between effectivity and toxicity of treatment strategies play a key role. Since comparative studies are lacking, a prospective randomized trial was designed among German AML study groups with different treatment strategies to compare outcome. Patients ≥60 years with all AML subtypes except M3 were randomized up-front to a common standard arm (CSA) (10%) and to study specific arms (90%) of the AMLCG or the OSHO. The CSA consisted of one or two inductions of araC 100 mg/m2/d continuous IV (CI) d 1-7 d and daunorubicin (dauno) 60 mg/m2/d IV d 3, 4, 5 and two courses of araC 1 g/m2/d BID IV d 1, 3 and 5 as consolidation (Mayer RJ et al, NEJM 1994). The AMLCG study arm randomized TAD (araC 100 mg/m2/d CI d1-2 followed by BID d 3-8, dauno 60 mg/m2/d IV d 3-5 and 6-thioguanine 100 mg/m2/d po BID d 3-9) and HAM [araC 1 mg/m2/d IV BID d 1-3 and mitoxantrone (mito) 10 mg/m2/d IV d 3-5] versus two courses of HAM with any 2nd course only given if blasts persisted ± G-CSF. Two courses of TAD were given as consolidation followed by maintenance chemotherapy over three years. The OSHO study arm included araC 1 g/m²/d BID IV d 1 + 3 + 5 + 7 and mito 10 mg/m2/d IV d 1 - 3 for one or two induction courses and ara-C 500 mg/m² BID 1h IV d 1 + 3 + 5 in combination with mito10 mg/m2/d IV d 1 + 2 as consolidation. Pegfilgrastim 6 mg s.c. was applied on day 10 of induction and on d 8 of consolidation. The study was approved by the IRB and registered at clinicaltrials.gov (NCT01497002 and NCT00266136). Written informed consent was obtained from all patients prior to randomization. Between April 1st, 2005 and May 26th, 2015 1286 patients were assigned randomly to the CSA (n=132) or to the study groups arm (n=1154). After excluding 139 patients (10.8%), 1147 patients were eligible for analysis, 1120 with follow-up for overall survival (OS) and 1079 for complete remission (CR) analysis. Baseline characteristics of all eligible patients showed median ages of 68 (60-82) years for the CSA and 69 (60-87) and 70 (60-85) years in the study arms A and B, respectively (p=0.05). Proportions of patients with secondary AML differed significantly between study arms (A: 42%, B: 30%, CSA: 36%; p=0.003). The CSA had less flt3 wildtype/npm1 wildtype patients (31%) vs. arm A (51% p=0.040) and arm B (58%, p=0.0455). No differences were observed with respect to cytogenetic risk groups, white blood cell counts, LDH, and npm1 mutant/ flt3-wildtype or mutant. The primary endpoint event free survival (EFS) did not differ between the CSA and study group strategies. Three-year EFS was 12.4% (95% CI: 6.7 - 19.9%) in the CSA, 15.6% (95% CI: 13.1 - 18.3%) in group A and 11.4% (95% CI, 7.4% to 16.4%) in group B (n.s.;Fig.1). With a median follow-up of 67 months, OS did not differ significantly between CSA and study group regimens. The 3-year survival probability was 22.3% (95% CI: 14.7-30.9%) in the CSA, 24.7% (95% CI: 21.6-27.9%) in group A and 22.4% (95% CI, 16.7% - 18.3%) in group B (Fig.2). CR status after 90 days of therapy was evaluated as secondary endpoint. The proportion of patients in CR in the CSA [51% (95% CI: 42-61%)] was comparable to the 50% (95% CI: 47-54%) and 48% (95% CI: 41-55%) of the study group arms (p=n.s.). Persistent leukemia was seen in 16% (95% CI: 10-24%) in the CSA vs 17% (95% CI: 14-19%) and 12% (95% CI: 8-17%) in groups A and B, respectively (both p= n.s.). A total of 226 patients died within 90 days of treatment, 24% (95% CI: 17-33%) in CSA, 19% in group A (95% CI: 16-22%) and 27% (95% CI: 21-33%) in group B; CSA vs A p=0.1859, CSA vs B p=0.5902). Death without AML was 3% in CSA, 2% in group A and 3% in group B, death with AML was 9% in CSA, 6% in group A and 5% in group B and death from indeterminate cause was 12% in CSA, 11% in group A and 20% in group B. Three-year relapse free survival (RFS) was 21.3% (95% CI: 12.2 - 31.0) in the CSA, 28.9% (95% CI: 24.9 -33.0%) in group A and 24.0% (95% CI: 16.8 - 31.9) in group B (both p=n.s.; Fig.3). In multivariate analysis independent variables for EFS and OS were age, type of disease, cytogenetic group and WBC count, but not the allocation to one of the treatment arms. Age and cytogenetic group were determinants for RFS. Conclusion A strictly prospective comparison of different treatment strategies in patients with AML did not show clinically relevant outcome differences when compared to a common standard arm. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Niederwieser: Novartis Oncology Europe: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Hoffmann:Novartis Oncology Europe: Research Funding. Al-Ali:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hegenbart:Pfizer: Other: Travel grant; Janssen: Honoraria, Other: Travel grant. Sayer:Riemser Pharma: Consultancy. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Fischer:Novartis: Consultancy, Honoraria. Dreger:Novartis: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Gilead: Speakers Bureau; Roche: Consultancy; Novartis: Speakers Bureau. Hiddemann:Roche: Membership on an entity's Board of Directors or advisory committees; Genentech: Other: Grants; Roche: Other: Grants.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.1066.1066

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 142, No. Supplement 1 ( 2023-11-02), p. 721-721

Abstract: Introduction: In 2022, the ELN risk classification for AML was updated for the second time. One of the major novelties of the ELN2022 is that all secondary-type mutations (STMs, i.e., mutations in the genes SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2) were now added to the adverse risk characteristics. However, a pertinent question also raised by the ELN expert panel is whether STMs abrogate the positive prognostic value of co-occurring, favorable NPM1 mutations. Aim: The aim of this study was to analyze the prognostic value of STMs in AML patients (pts) who also harbor an NPM1 mutation. Methods: We investigated a pooled cohort of 936 NPM1-mutated AML pts who were treated in previously reported multicenter trials of the Study Alliance Leukemia or the AML Cooperative Group. Eligibility was determined based on diagnosis of non-APL, age ≥ 18 years, NPM1 mutation detected in targeted sequencing, curative treatment intent, and available biomaterial at diagnosis. Standard techniques for chromosome banding and fluorescence-in-situ-hybridization (FISH) were used for karyotyping. Next-generation panel sequencing was performed to detect genetic alterations that are recurrently found in myeloid neoplasms. Results: In our multicenter cohort of 936 NPM1-mutated AML pts, median follow-up for the entire cohort was 8.0 years. We found 125 patients (13.4%) harboring at least one STM ( SRSF2 [n=48; 5.1%], STAG2 [n=32; 3.2%] , EZH2 [n=22, 2.4%], BCOR [n=16; 1.7%] , SF3B1 [n=13; 1.4%], ASXL1 [n=12; 1.3%] , ZRSR2 [n=5; 0.5%], and U2AF1 [n=4; 0,4%] ). A comparison of pretreatment clinical and genetic features revealed that pts with a STM were significantly older ( p=.003, median 59 vs. 55 years), had lower white blood cell counts ( p & lt;.001, 22.2*10 9/L vs. 39.7*10 9/L,) and platelet counts ( p & lt;.001, 46.5*10 9/L vs. 65.0 10 9/L). The strongest pair-wise associations between gene mutations were observed between U2AF1 and RUNX1 ( p & lt;.001) as well as SRSF2 and IDH2 ( p & lt;.001). With respect to outcome, complete remission (CR) rate did not differ significantly between NPM1-mutated patients with or without additional STMs ( p=.41, 74.4% vs. 77.7%, OR 0.83 [95%-CI 0.54-1.29]). Median RFS for NPM1-mutated pts with STMs was 32.9 months (95%-CI: 13.0-46.0) while patients without STMs had a median RFS of 24.3 months (95%-CI: 18.7-33.3) corresponding to a HR of 1.04 ( p=0.80, 95%-CI 0.79-1.37; Figure A). Median OS for NPM1-mutated pts with or without STMs was 27.2 months (95%-CI: 14.2-49.0) and 29.1 months (95%-CI: 23.5-41.4), respectively, corresponding to a HR of 1.11 ( p=.37, 95%-CI 0.88-1.41; Figure B). To focus solely on the impact of STMs, we subsequently excluded patients with co-occurring mutations in TP53 or myelodysplasia-related cytogenetics, which all define an ELN adverse risk. Again, we observed no differences in CR rate ( p=.54, 78% vs. 75.4%), RFS ( p=.59, median 33.2 months vs. 26.6 months), or OS ( p=.33, median 27.4 month vs. 32.6 month) between NPM1-mutated patients with or without STMs. Next, we restricted our analysis to pts who are classified favorable risk according to ELN2022. Again, we found no significant outcome differences based on the STM status (unmutated vs. mutated: CR rate, 80% vs. 70.7% [ p=.072]; RFS, median 49.7 months vs. 46.0 months [ p=.702] ; OS, median 45.3 months vs. 59.8 months [ p=.092]). Conclusion: NPM1 mutations rank as the second most frequent mutations in AMLand the most common in patients with a normal karyotype and serve as an established favorable prognostic marker. Our data from a large cohort demonstrate that additional STMs have no adverse effect on the clinical outcome of NPM1-mutated patients. As a result, these patients should still be considered ELN favorable risk.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2023-186160

Language: English

Publisher: American Society of Hematology

Publication Date: 2023

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2723-2723

Abstract: Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown. We performed whole-exome and genome sequencing of tumor and matched germline control samples from 11 patients with locally advanced or metastatic chordoma within the MASTER program, a prospective clinical sequencing program of the German Cancer Consortium. All patients were pretreated and had progressive disease prior to molecular analysis. Genomic profiling showed that advanced chordomas are frequently characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair. First, DNA copy number profiles showed high numbers of structural variants greater than 10 million base pairs in size in the majority of cases. Second, all patients harbored somatic aberrations of at least 2 genes known to be involved in HR, and 10/11 cases harbored somatic alterations in 3 or more HR pathway genes. For example, 8 patients showed heterozygous BRCA2 deletions, which were associated with heterozygous deletions of ERCC6 in 6 patients and RAD54L in 7 patients, as well as PTEN alterations (heterozygous deletion, heterozygous mutation and deletion of the wildtype allele or loss of heterozygosity). Other recurrently altered HR genes included ATR, CHEK2, FANCC, FANCD2, FANCG, RAD18, RAD51B, and XRCC3. Third, pathogenic germline alterations were detected in 3 patients. A heterozygous BRCA2 frameshift mutation (p.T3085fs*26; ACMG Class 5), a heterozygous NBN frameshift mutation (p.K219Nfs*16; ACMG Class 5), and a heterozygous CHEK2 missense mutation (p.R145W; ACMG Class 4) were accompanied by somatic deletion of the respective wildtype alleles. Fourth, a mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and coincided with genomic instability. The high prevalence of an HR deficiency “footprint” in chordoma patients prompted us to explore the clinical efficacy of the poly(ADP-ribose) polymerase(PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells. Olaparib treatment of a patient whose tumor showed a prominent exposure to an HR deficiency-associated mutational signature, a high degree of genomic instability, and 13 heterozygous HR gene alterations halted tumor growth for 10 months. Whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain, providing novel insight into the mechanisms of PARP inhibitor resistance. In summary, our study has uncovered a key biological feature of advanced chordoma that represents an immediately actionable therapeutic target and provides a rationale for genomics-guided clinical trials of PARP inhibition in this intractable tumor entity. Citation Format: Stefan Gröschel, Daniel Hübschmann, Francesco Raimondi, Peter Horak, Gregor Warsow, Martina Fröhlich, Barbara Klink, Laura Gieldon, Barbara Hutter, Kortine Kleinhenz, David Bonekamp, Oliver Marschal, Priya Chudasama, Jagoda Mika, Marie Groth, Sebastian Uhrig, Stephen Krämer, Christoph Heining, Christoph Heilig, Daniela Richter, Eva Reisinger, Katrin Pfütze, Roland Eils, Stephan Wolf, Christof von Kalle, Christian Brandts, Claudia Scholl, Wilko Weichert, Stephan Richter, Sebastian Bauer, Roland Penzel, Evelin Schröck, Albrecht Stenzinger, Richard Schlenk, Benedikt Brors, Robert Russell, Hanno Glimm, Matthias Schlesner, Stefan Fröhling. Defective homologous recombination DNA repair as therapeutic target in advanced chordoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2723.

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2019-2723

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2019

detail.hit.zdb_id: 2036785-5

detail.hit.zdb_id: 1432-1

In: Journal of Hematology & Oncology, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2022-09-05)

Abstract: The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups ( IDH1 R132C, R132H and  IDH2  R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants  IDH1  R132C and  IDH2  R172K showed a significant benefit from alloHCT for OS ( p  = .017 and p  = .049) and RFS (HR = 0.42, p  = .048 and p  = .009) compared with chemotherapy only. AlloHCT in  IDH2  R140Q mutated AML resulted in longer RFS (HR = 0.4, p  = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

Type of Medium: Online Resource

ISSN: 1756-8722

URL: Article

DOI: 10.1186/s13045-022-01339-8

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2429631-4