GLORIA

GEOMAR Library Ocean Research Information Access

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Material
Language
Subjects(RVK)
  • 1
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2345-2345
    Abstract: Background: Accurate prediction of response to induction chemotherapy and survival is essential for improving care of AML patients. Established prognostic schemes in AML are based on 1) clinical features and 2) pre-treatment karyotype. More recently molecular markers have been shown to be of prognostic importance. Correlation between DNA methylation in leukemic cells and clinical prognosis has been described but is not assessed routinely in clinical practice due to lack of a clinical assay. Here we report the ability of a novel, clinically feasible assay of DNA methylation status to predict clinical outcomes in AML patients. Methods: A novel microsphere-based assay for multiplex evaluation of DNA methylation (xMELP) was used to simultaneously measure methylation status at multiple prognostic loci in banked AML samples. A methylation risk score (M score) was assigned to each sample using a 17-locus random forest classifier developed using an independent cohort. Cytogenetic risk was assigned to each sample using the MRC schema (Grimwade et al. Blood 2010). The primary clinical endpoints were failure to achieve complete remission (CR) within 90 days of induction and death before 2-years (2-year death). The receiver operating characteristic (ROC) curve was used to evaluate the performance of the M-score as prognostic biomarker. Univariate and multivariate logistic models were used to assess the ability of the M-score to predict 2-year death in combination with co-variates. Results: This study included 101 patients with de novo AML age 〈 60 years with diagnostic samples available for xMELP analysis who underwent induction therapy at the University of Pennsylvania (2001-2012). The median age was 48 years (range 19-59), the median WBC count at diagnosis was 34.5 K/uL (range .8 -283.5 K/uL; 20% ≥100K/uL), and 55% were male. The majority of patients had intermediate cytogenetic risk (13% favorable, 65% intermediate, 18% unfavorable, 4% unknown). Among the study patients, 25% did not achieve CR and 52% died within 2 years of diagnosis. The mean M-scores for the entire population were 84.6 (SD 30.3) versus 104.9 (SD 29.3) for those who achieved and failed to achieve CR, respectively (p=.004) while the mean M-scores were 77.5 (SD 24.7) versus 100.5 (SD 32.7) for those alive and dead at 2 years, respectively (p=.002). Within the intermediate cytogenetic risk group, results were similar: the mean M-scores were 87.3 (SD 31.8) versus 105.1 (SD 29.6) for those who achieved and failed to achieve CR, respectively (p=.06) and the mean M-scores were 78.9 (SD 25) versus 101.2 (SD 33.9) for those alive and dead at 2 years, respectively (p=.004). The M-score was not associated with sex or WBC at diagnosis, but it differed significantly among the 4 cytogenetic risk groups (ANOVA p=.01) with a higher M-score in less favorable cytogenetic groups. The area under the ROC curve (AUC) was .69 for failure to achieve CR (95% CI .58-.80) and .71 (95% CI .61-.81) for 2-year death. For AML patients with intermediate cytogenetic risk, the AUC was .66 (95% CI .52-.80) for failure to achieve CR and .70 (95% CI .57 to .82) for 2-year death. For the cohort overall, the odds ratios for failure to achieve CR and 2-year death were 1.02 (p=.007) and 1.03 (p=.001), respectively, indicating that every 1-point rise in the M-score resulted in a 2% higher chance of not achieving CR and a 3% greater chance of dying by 2 years. We investigated the ability of the M-score to predict 2-year death in combination with other prognostic co-variates. Adding age, diagnostic WBC count, and cytogenetic risk to the prognostic model did not improve prediction of 2-year death. A model incorporating M-score and CR did predict 2-year death better than M-score alone (AUC .80 versus AUC .71, p=.005). Results were similar when restricting analysis to intermediate cytogenetic risk group (AUC .77 versus AUC .70, p=.048). Conclusion: There is a clinical need for predictive biomarkers in AML. Here, we show that a novel method of measuring methylation in AML predicts failure to achieve CR and likelihood of death within 2 years. A model incorporating methylation and remission status was better for prediction of 2-year death than a model with only methylation information. Although validation in additional cohorts is necessary, these results demonstrate the feasibility and benefit of clinical application of a multiplex DNA methylation assay to survival prognostication in AML. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 2
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2046-2046
    Abstract: Having observed an unexpectedly high rate of acute cholecystitis following allogeneic hematopoietic stem cell transplantation (allo-HCT), we sought to define the risk factors for development of acute cholecystitis following allo-HCT, as well as the incidence, radiographic presentation, and outcomes of this disease in the transplant population. Methods Between January 2001 and December 2011, 644 patients underwent allo-HCT at our institution. Using ICD-9 codes, we screened this population for a diagnosis of acute cholecystitis or for cholecystectomy in the first year following HCT. Cases were confirmed through manual chart review, and were defined as having one or more imaging modalities positive for acute cholecystitis or having surgical gallbladder pathology consistent with acute cholecystitis. We then conducted a nested case-control study with controls randomly selected through incidence density sampling of the transplant cohort at a rate of 3:1, matching for age and sex. Using logistic regression, we evaluated multiple potential risk factors for the development of acute cholecystitis, including underlying hematologic malignancy, graft-versus-host-disease (GVHD), total parenteral nutrition (TPN) use, graft source, ABO incompatibility, 〉 10% weight loss, conditioning regimen, and cytomegalovirus reactivation. Finally, we conducted a separate case-control study to evaluate the effectiveness of multiple radiographic studies in the diagnosis of acute cholecystitis in HCT recipients (n=32) compared to randomly selected non-transplant control patients who were diagnosed with acute cholecystitis at our institution (n=96). Results The incidence of acute cholecystitis in the first year of transplant was 5.0% (32/644 patients). Of the 32 patients, 21 (65.6%) were male and 11 (34.4%) were female with a median age of 52.2 years (range, 24–75 years). Median time from HCT to diagnosis of acute cholecystitis was 56.5 days (range, 6–342 days). Twenty of 32 patients (62.5%) were treated with cholecystectomy, 7 (21.9%) with percutaneous cholecystostomy drainage, and the remaining 5 (15.6%) with conservative medical management. Twenty of the 32 patients who developed acute cholecystitis died within one year of HCT (62.5%), compared with 19 of 96 control patients (19.8%), (p 〈 0.001). Of the 20 cholecystitis patients who died, three (15%) died as a direct result of acute cholecystitis; cause of death was septic shock in all 3 cases. HCT patients who received TPN had a higher risk of developing acute cholecystitis (multivariate OR, 3.41; p=0.009), while development of GVHD was protective against developing acute cholecystitis (multivariate OR, 0.28; p=0.006). When accounting only for development of grade III-IV GVHD, a trend towards protection remained but was not statistically significant (OR, 0.24; p=0.061). Ultrasound findings were equivocal for acute cholecystitis (vs. definitively positive or negative) more frequently in allo-HCT patients than in non-HCT patients (50.0% vs. 30.6%), although this difference was not statistically significant (p=0.063). Of the 32 case patients, 30 (93.8%) had US performed, and of these only 13 (43.3%) had an US positive for acute cholecystitis. Computed tomography (CT) scan was equivocal (versus definitively positive or negative) for acute cholecystitis at similar rates in allo-HCT and non-HCT patients (54.7%, vs. 41.2%, p=0.331), and cholescintigraphy (HIDA) scan was positive for cholecystitis at similar rates in both populations (80.0% vs. 77.4%, p=0.82). Conclusions Acute cholecystitis is a common complication of allo-HCT, especially in patients who received TPN. It is associated with a high 1-year mortality rate, and abdominal US has suboptimal performance in diagnosing it. Our data suggest that a high index of suspicion and use of alternative imaging modalities are required to make a prompt diagnosis and may improve the outcomes of allo-HCT patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 3
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 21, No. 4 ( 2015-04), p. 768-771
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 21, No. 7 ( 2015-04-01), p. 1614-1620
    Abstract: Purpose: DNA methyltransferase 3A (DNMT3A) is one of the commonly mutated genes in acute myelogenous leukemia (AML). Reports on the prognostic significance of DNMT3A mutations have been inconsistent, and most of the data are available only for patients 60 years of age or younger. We hypothesized that this inconsistency is due to an interaction between the dose of anthracycline used in induction therapy and DNMT3A status. We studied whether patients with DNMT3A-mutated AML treated with standard dose anthracyclines had an inferior survival compared with patients with other mutation profiles or those who received high-dose therapy. Experimental Design: A total of 152 patients in this retrospective cohort study (median age, 54 years) with de novo AML underwent induction therapy and next-generation sequencing of 33 commonly mutated genes in hematologic malignancies, including DNMT3A, FLT3-ITD, NPM1, and IDH1/2. Cox regression was used to know whether those with DNMT3A mutations who were treated with standard dose anthracycline had inferior survival. Results: DNMT3A mutations, found in 32% of patients, were not associated with an inferior survival. Dose escalation of anthracycline in the induction regimen was associated with improved survival in those with DNMT3A mutations but not those with wild-type DNMT3A. Patients with DNMT3A mutations who received standard dose induction had shorter survival time than other patient groups (10.1 months vs. 19.8 months, P = 0.0129). This relationship remained significant (HR, 1.90; P = 0.006) controlling for multiple variables. Conclusions: Patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy. This group should be considered for high-dose induction therapy. Clin Cancer Res; 21(7); 1614–20. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 5
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 26, No. 3 ( 2020-03), p. S25-S26
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 7515-7515
    Abstract: 7515 Background: POD24 is an indicator of poor survival in iNHL (Casulo & Barr. Blood. 2019). In the ZUMA-5 Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL, overall response rates (ORR) after 17.5 months median follow-up were similarly high in those with and without POD24 (93% and 92%; Jacobson et al. ASH 2020. #700). Here, we report updated outcomes with longer follow-up in pts with POD24 in ZUMA-5. Methods: Adults with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy underwent leukapheresis followed by conditioning therapy and axi-cel infusion (2×10 6 CAR T cells/kg). Axi-cel–treated pts with available data on progression after an anti-CD20 mAb + alkylating agent were included. The updated efficacy analysis occurred when ≥80 treated pts with FL had ≥18 months follow-up. Results: Of 129 pts at baseline, 81 pts (63%; 68 FL, 13 MZL) had POD24 and 48 pts (37%; 40 FL, 8 MZL) did not have POD24. Median prior lines of therapy in pts with and without POD24 were 3 and 3.5, respectively. High-risk characteristics of pts with and without POD24 included stage III/IV disease, 83% and 94%; ≥3 FLIPI, 44% and 43%; high tumor bulk (GELF), 51% and 44%; and refractory disease, 77% and 63%, respectively. With 23.3 months median follow-up, ORR among efficacy-evaluable pts with POD24 (n = 61) and without POD24 (n = 37) was 92% each (complete response rates, 75% and 86%). At data cutoff, 52% of pts with POD24 and 70% without POD24 had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached in pts with and without POD24; 18-month estimated rates were 60% and 78%, 55% and 84%, and 85% and 94%, respectively. Incidences of Grade ≥3 adverse events were similar in pts with and without POD24 (84% and 88%), including cytopenias (69% and 65%) and infections (15% and 21%). Grade ≥3 cytokine release syndrome (CRS) occurred in 9% and 2% of pts with and without POD24, respectively; Grade ≥3 neurologic events (NEs) occurred in 17% of pts each. Median times to onset were similar in pts with and without POD24 for CRS (4 days each) and NEs (8 days and 7 days); median durations of CRS (7 days and 5 days) and NEs (11 days and 13 days) were also similar between groups. In efficacy-evaluable pts with FL, median peak CAR T-cell levels were similar in pts with and without POD24 (35.8 cells/μL and 34.5 cells/μL). Peak levels of key inflammatory biomarkers and axi-cel product attributes were generally similar in pts with and without POD24. Conclusions: Axi-cel showed a high rate of durable responses in pts with POD24 iNHL, a population with high-risk disease. Efficacy results, as well as safety and pharmacological profiles, appeared largely comparable between groups, with the exception of PFS rates. Clinical trial information: NCT03105336.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 7548-7548
    Abstract: 7548 Background: ZUMA-5 is a Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL (follicular lymphoma [FL]; marginal zone lymphoma [MZL] ). In the primary analysis, 11 pts (9 FL; 2 MZL) were retreated with axi-cel, achieving an overall response rate (ORR) of 100% (91% complete response [CR] rate) at a median follow-up of 2.3 mo post-reTx, with no Grade ≥3 cytokine release syndrome (CRS) or neurologic events (NEs; Chavez et al. ASH 2020. #2036). Here, we report updated clinical and translational outcomes with longer follow-up in pts retreated with axi-cel in ZUMA-5. Methods: Eligible pts with FL or MZL had R/R disease after ≥2 lines of therapy. Pts were considered for reTx if they progressed after a response at mo 3, had no evidence of CD19-negative relapse in biopsy, had no axi-cel neutralizing antibodies, and had no Grade 4 CRS or NEs with 1st Tx. Retreatment was per investigator discretion. At both Txs, pts received axi-cel (2×10 6 CAR T cells/kg) after conditioning chemotherapy. Results: As of 9/14/2020, 13 pts with iNHL (11 FL; 2 MZL) received axi-cel reTx, with 2 pts retreated after the primary analysis. Before their 1st Tx, pts had median 4 prior lines of therapy; 85% had stage 3–4 disease; 82% had FLIPI of ≥3; 46% were POD24; 77% had refractory disease. Among the 13 retreated pts, 85% had a CR to 1st Tx. Median 1st duration of response (DOR) was 8.2 mo. Detectable CD19 was confirmed in all evaluable biopsies from retreated pts at relapse, and median time from 1st Tx to reTx was 10.6 mo. Following reTx, the ORR was 100% (77% CR rate). After a median follow-up of 11.4 mo, the median DOR had not yet been reached; 46% of retreated pts had ongoing responses at data cutoff. At 1st Tx, CRS occurred in 9 pts (5 Grade 1, 4 Grade 2); NEs occurred in 5 (3 Grade 1, 1 Grade 2, 1 Grade 3). At reTx, CRS occurred in 8 pts (6 Grade 1, 2 Grade 2); NEs occurred in 4 (3 Grade 1, 1 Grade 2). Median peak levels of biomarkers typically associated with severe CRS and NEs were similar at reTx and 1st Tx (IL-6, 7.7 vs 5.7 pg/mL; IL-2, 1.8 vs 0.9 pg/mL; IFN-γ, 62.9 vs 64.2 pg/mL). In the 11 retreated pts with FL, tumor burden (median sum of product diameters [SPD] ) was lower before reTx vs 1st Tx (1416 vs 4770 mm 2 ). Engraftment index (CAR T-cell expansion relative to SPD) is an indirect proxy for effector:target ratio and a key covariate of response to axi-cel (Locke et al. Blood Adv. 2020). Though median peak CAR T-cell levels appeared lower at reTx vs 1st Tx (5.2 vs 14.3 CAR+ cells/µL blood), engraftment index was similar (0.003 vs 0.005 cells/µL×mm2). Conclusions: Axi-cel reTx achieved deep and durable responses, with an acceptable safety profile. Tumor CD19 positivity was maintained at relapse, and engraftment index was similar at both Txs, comparing favorably to previous reports in aggressive lymphomas (Locke et al. ASCO 2020. #8012). These data suggest axi-cel reTx is a promising option for pts with R/R iNHL. Clinical trial information: NCT03105336.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 7068-7068
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 9
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 59, No. 11 ( 2018-11-02), p. 2595-2601
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2018
    detail.hit.zdb_id: 2030637-4
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 7062-7062
    Abstract: 7062 Background: Pts with R/R LBCL after first-line (1L) treatment (tx) who are unable to undergo high-dose chemotherapy (HDCT) and HSCT have poor outcomes and limited tx options. PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. Methods: Eligible pts were adults with R/R LBCL after 1L tx who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF 〈 50%, CrCl 〈 60 mL/min, or ALT/AST 〉 2 × ULN. Bridging tx was allowed. Pts received lymphodepletion with cyclophosphamide and fludarabine, followed 2–7 days later by liso-cel at a target dose of 100 × 10 6 CAR + T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria and neurological events (NE) per NCI CTCAE, version 4.03. Primary endpoint was ORR per independent review committee (IRC); all pts had ≥ 6 mo follow-up (f/u) from first response. Results: Of 74 pts leukapheresed, 61 received liso-cel and 1 received nonconforming product. Common reasons for pre-infusion dropout included death and loss of eligibility (5 each). For liso-cel–treated pts, median age was 74 yr (range, 53–84; 79% ≥ 70 yr) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectively; 26% had ECOG PS = 2 and 44% had HCT-CI score ≥ 3. After 1L tx, 54% were chemotherapy refractory, 21% relapsed ≤ 12 mo, and 25% relapsed 〉 12 mo; 51% of pts received bridging chemotherapy. Median (range) on-study f/u was 12.3 mo (1.2–26.5). ORR and CR rate was 80% and 54%, respectively. Median DOR and PFS was 12.1 mo and 9.0 mo, respectively. Median OS has not been reached (Table). Most frequent tx-emergent AEs (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade (gr) 3 CRS in 1 pt (2%) and no gr 4/5 CRS. Any-grade NEs were seen in 31%, gr 3 in 5% (n = 3), and no gr 4/5 NEs; 7% received tocilizumab, 3% corticosteroids, and 20% both for tx of CRS/NEs. Overall, gr ≥ 3 TEAEs occurred in 79%, with gr 5 in 2 pts (both due to COVID-19). Two pts (3%) had gr 3/4 infections and 15 (25%) had gr ≥3 neutropenia at Day 29. Conclusions: In the PILOT study, liso-cel as 2L tx in pts with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable overall and complete responses, with no new safety concerns. Clinical trial information: NCT03483103. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...