Kooperativer Bibliotheksverbund

In: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 107, No. 12 ( 2015-12), p. djv279-

Type of Medium: Online Resource

ISSN: 0027-8874 , 1460-2105

URL: Article

DOI: 10.1093/jnci/djv279

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2015

detail.hit.zdb_id: 2992-0

detail.hit.zdb_id: 1465951-7

In: Nature Communications, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2016-03-09)

Abstract: Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES , P =2.55 × 10 −11 ), 6p25.2 (rs73718779, SERPINB6 , P =1.97 × 10 −8 ) and 3q28 (rs9815073, LPP , P =3.62 × 10 −8 ), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11 , P =1.00 × 10 −11 ) in the combined analysis. We find suggestive evidence ( P 〈 5 × 10 −7 ) for two additional new loci at 4q24 (rs10028805, BANK1 , P =7.19 × 10 −8 ) and 3p22.2 (rs1274963, CSRNP1 , P =2.12 × 10 −7 ). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/ncomms10933

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2016

detail.hit.zdb_id: 2553671-0

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 58, No. 6 ( 2017-06-03), p. 1376-1383

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428194.2016.1251592

Language: English

Publisher: Informa UK Limited

Publication Date: 2017

detail.hit.zdb_id: 2030637-4

In: American Society of Clinical Oncology Educational Book, American Society of Clinical Oncology (ASCO), , No. 41 ( 2021-06), p. e339-e353

Abstract: Optimizing the well-being of the oncology clinician has never been more important. Well-being is a critical priority for the cancer organization because burnout adversely impacts the quality of care, patient satisfaction, the workforce, and overall practice success. To date, 45% of U.S. ASCO member medical oncologists report experiencing burnout symptoms of emotional exhaustion and depersonalization. As the COVID-19 pandemic remains widespread with periods of outbreaks, recovery, and response with substantial personal and professional consequences for the clinician, it is imperative that the oncologist, team, and organization gain direct access to resources addressing burnout. In response, the Clinician Well-Being Task Force was created to improve the quality, safety, and value of cancer care by enhancing oncology clinician well-being and practice sustainability. Well-being is an integrative concept that characterizes quality of life and encompasses an individual's work- and personal health–related environmental, organizational, and psychosocial factors. These resources can be useful for the cancer organization to develop a well-being blueprint: a detailed start plan with recognized strategies and interventions targeting all oncology stakeholders to support a culture of community in oncology.

Type of Medium: Online Resource

ISSN: 1548-8748 , 1548-8756

URL: Article

DOI: 10.1200/EDBK_320873

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2021

detail.hit.zdb_id: 2431126-1

In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 1919-1919

Abstract: Genetic analysis has an increasing role in the diagnosis, classification, and management of patients with CLL. Although translocations involving the IgH locus are well characterized in B-cell malignancies such as follicular cell lymphoma, their frequency and significance in CLL are less well defined. We studied a series of patients with a clinical diagnosis of CLL using a FISH probe set including IgH. Methods: FISH was performed on blood using a DNA probe set designed to detect common chromosome anomalies associated with CLL and translocations involving IgH. Patients with an IgH abnormality were further studied using FISH probes sets for IgH and cyclin D1, BCL-2, BCL-3, BCL-6, BCL-11a, c-MYC, MALT-1, c-MAF, FGFR-3 or PAX-5. The clinical presentation, pathology, and flow cytometric immunophenotype was reviewed in patients with various translocations involving IgH. Results: Between 1/1/03 and 6/15/04, samples from 1032 patients with a clinical diagnosis of CLL were analyzed by FISH. Of these, 76 patients (7%) had translocations involving the IgH locus. Sixty one patients had a single translocation partner gene (cyclin D1 45%, BCL-2 24%, BCL-3 8%, c-MYC 2.5%, or BCL-11a 1.3%). Two patients had two independent clones (cyclin D1 and BCL-2; BCL-3 and BCL-11a). In 13 pts (17%) we could not identify the translocation partner. Thirty five (46%) of the 76 patients with IgH translocations had been seen at Mayo Clinic Rochester and had clinical and laboratory data for detailed review. Among these 35 patients, 16 (45%) had fusion of IgH and cyclin D1 and were diagnosed with mantle cell lymphoma (MCL). The immunophenotype of the monoclonal B cells was typical of MCL (CD5+, CD23-) in 6 patients and typical of CLL (CD5+, CD23+) in 4 patients. Six MCL patients had non-diagnostic immunophenotypes: CD5-, CD 23+ (n = 3) and CD5-, CD23- (n = 3). Twelve (34%) of the 35 patients had the IGH/BCL-2 fusion gene. Of these, 3 patients had leukemic phase follicular lymphoma, one had both CLL and MCL, and 8 had the diagnostic immunophenotype of CLL. The remaining 7 patients (19%) had a variety of translocation partners: BCL-3 (n = 1), BCL-3 and BCL-11a (n = 1), c-MYC (n = 2), and unknown (n = 3). The patients with a translocation involving BCL-3 had a typical CLL immunophenotype. Discussion: The IgH FISH probe detected a molecular defect in 7% of patients with a circulating monoclonal B cell population. In patients with a CLL immunophenotype, use of the IgH probe identified the IgH/cyclin D1 translocation characteristic of MCL in 4 patients, a finding of major clinical significance. Interestingly, after exclusion of MCL patients, more than 4% patients with CLL had other translocations involving IgH, a proportion comparable with other better defined chromosomal abnormalities in CLL. Although IgH/BCL-2 translocation is usually associated with follicular lymphoma, we identified 8 patients with CLL and this translocation. Translocations involving BCL-3 had been described before in CLL with an “atypical” immunophenotype. In contrast both of our patients with BCL-3 had typical phenotypes. Translocations involving IgH and BCL-11a have not been previously described. We conclude that FISH studies using the IgH probe improve the precision of diagnosis in CLL and could also have prognostic value.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V104.11.1919.1919

Language: English

Publisher: American Society of Hematology

Publication Date: 2004

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Mayo Clinic Proceedings, Elsevier BV, Vol. 83, No. 7 ( 2008-7), p. 776-785

Type of Medium: Online Resource

ISSN: 0025-6196

URL: Article

DOI: 10.4065/83.7.776

Language: English

Publisher: Elsevier BV

Publication Date: 2008

detail.hit.zdb_id: 2052617-9

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 717-717

Abstract: Introduction: Ibrutinib has shown remarkable safety and efficacy in CLL. Due to CYP3A4 (3A4) metabolism, the concurrent use of 3A4 inhibitors/inducers with ibrutinib should be avoided. Ibrutinib is also associated with bleeding complications, in part due to effects on collagen-mediated platelet aggregation, thus caution is advised with the simultaneous use of anticoagulant (AC) and antiplatelet agents. It is unknown what proportion of CLL patients starting ibrutinib therapy in routine practice are on these medications. We conducted a retrospective study to evaluate these aspects in a large cohort of CLL pts treated with ibrutinib outside the context of clinical trials. Methods: Following IRB approval, consecutive CLL pts who initiated ibrutinib off-protocol at Mayo Clinic, Rochester, MN from November 2013 through July 2015 were evaluated. A medication review for drug-drug interactions was performed by a pharmacist on all pts. Baseline characteristics, concomitant medications, and toxicity were recorded. Time to toxicity and ibrutinib discontinuation were analyzed by Kaplan Meier and cumulative incidence methods accounting for competing risk of death, respectively. Results: Ninety-six CLL pts started ibrutinib. Median age was 66 years and 64 (67%) were male. Ibrutinib indications included: relapsed/refractory CLL (n=84), treatment-naïve CLL with del17p (n=8), and CLL with Richter's transformation (n=4). Approximately 80% had unmutated IGHV and 45% had del17p or del11q on FISH. Upon initial pharmacy consult prior to ibrutinib, the median number of concomitant medications was 9 (range, 1-31). Sixty (63%) pts were taking concurrent medications increasing their risk of ibrutinib toxicity and 4 (4%) pts were on drugs potentially reducing ibrutinib efficacy. At ibrutinib initiation, 16 (17%) pts were on concomitant 3A4 inhibitors. This included 9 (9%) on moderate 3A4 inhibitors (fluconazole, diltiazem, imatinib, cyclosporine) and 7 (7%) on strong 3A4 inhibitors (voriconazole, posaconazole, clarithromycin, itraconazole). In 4 pts, the 3A4 inhibitor was switched to another agent or discontinued to allow standard 420 mg daily dosing. Ibrutinib was initiated at 140 mg daily in 7 pts on moderate 3A4 inhibitors and at 140 mg every 48 hours in 5 pts on strong 3A4 inhibitors. Four (4%) pts were on strong 3A4 inducers (carbamazepine, rifampin, rifabutin) at the initiation of ibrutinib. The 3A4 inducer was discontinued prior to ibrutinib start in 3 pts, while the initial ibrutinib dose was decreased to 140 mg every 48 hours in the remaining patient (also on 2 strong 3A4 inhibitors). During the course of ibrutinib, an additional 8 (8%) pts were started on 3A4 inhibitors/inducers which necessitated dose modifications. Upon commencing ibrutinib, 9 (9%) pts were on concomitant AC (6 warfarin, 3 enoxaparin). Due to significant bleeding risk, warfarin was switched to enoxaparin in 2 pts, to aspirin (ASA) in 1 and warfarin was discontinued in 1. In 2 pts, an alternative AC could not be used so ibrutinib was begun at 140 mg daily and titrated upward. Twenty-nine (30%) pts were on ASA (3 [3%] also on clopidogrel) at ibrutinib initiation. Nineteen (20%) pts were on selective serotonin release inhibitors (SSRIs), and 9 (9%) were on NSAIDs. Thirteen (13%) pts were on fish oil and 24 (25%) were on herbal medications; all of which were discontinued prior to starting ibrutinib. Ten (10%) pts had clinically significant bleeding on ibrutinib including 4 (4%) requiring hospitalization (1 subdural hematoma). Of these 4 pts, 1 was on enoxaparin, 2 were on a SSRI and 1 a NSAID. Six pts had minor bleeding necessitating a dose reduction of ibrutinib to 140-280 mg daily. After 16 months follow-up, the risk of bleeding was 21% (95% CI: 1-37%, Figure). After a median follow-up of 7.6 months, 73 (76%) pts remain on ibrutinib. There was no difference in rates of discontinuation of ibrutinib between patients who were on 3A4 inhibitors/inducers versus those who were not. Conclusion: In the "real-world" setting, 2 out of 3 CLL patients commencing ibrutinib therapy is on a concomitant medication with a potentially clinically significant drug-drug interaction with ibrutinib. These findings have implications for the practicing hematologist who must maintain a high degree of vigilance when prescribing ibrutinib to CLL pts. We highly recommend a formal medication review by a clinical pharmacist in all patients initiating ibrutinib. Figure 1. Figure 1. Disclosures Ding: Merck: Research Funding. Kay:Hospira: Research Funding; Tolero Pharma: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shanafelt:Glaxo-Smith_Kline: Research Funding; Pharmactckucs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.717.717

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. 132, No. Supplement 1 ( 2018-11-29), p. 4394-4394

Abstract: Introduction: Several prognostic models for overall survival (OS) in chronic lymphocytic leukemia (CLL) have been developed, but none were derived for patients (pts) with relapsed or refractory (R/R) CLL treated in the era of novel agents. We used a comprehensive approach to derive and validate a novel risk model for OS in 2,475 pts with R/R CLL who received therapy in randomized phase 3 trials evaluating ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) vs control arms, or the Mayo Clinic CLL Database (MCCD). Methods: In collaboration with Janssen, Gilead, Pharmacyclics, and Genentech/Roche, the analysis included 2,475 pts from 6 multicenter randomized phase 3 trials or the MCCD. Trials included were: IBR plus bendamustine-rituximab (BR) vs placebo plus BR (HELIOS: NCT01611090), IBR vs ofatumumab (RESONATE: NCT01578707), IDELA plus BR vs placebo plus BR (Study 115: NCT01569295); IDELA plus rituximab vs placebo plus rituximab (Study 116: NCT01539512); IDELA plus ofatumumab vs ofatumumab (Study 119: NCT01659021); VEN plus rituximab vs BR (MURANO: NCT02005471). All pts had R/R CLL and required treatment by iwCLL criteria. The model-building dataset (n=969) included pts from HELIOS and RESONATE, and was randomly assigned to the IBR/chemoimmunotherapy (CIT) training dataset (n=727) and IBR/CIT internal-validation dataset(n=242). Three independent external validation datasets included IDELA/CIT (n=897), VEN/CIT (n=389), and MCCD (n=220). We applied univariate and multivariate analyses (MVA) to 28 candidate clinical/laboratory and genetic prognostic factors to derive the risk model in the training dataset. The primary endpoint was OS. We assessed the need for separate models for targeted agents by interactions with treatment in univariate analyses. We proceeded to develop a single model for all pts with R/R CLL, as only one candidate factor (del(13q), interaction p value 〈 0.1) demonstrated a marginal differential effect. We evaluated cutoffs for dichotomized covariates and for definition of risk groups after the final factors were selected. We fit a Cox regression on the training and internal/external validation datasets using the risk categories as the covariate to test the difference among the groups, and calculated the C-statistic as a measure of discrimination. Results: Of 11 selected factors with a significant univariate effect on OS (p 〈 0.1), 6 were independently prognostic in the MVA of OS (p 〈 0.05): Baseline β2-microglobubulin (B2M), lactate dehydrogenase (LDH), hemoglobin (HGB), IGHV mutational status, number of prior therapies, and time from initiation of last therapy. We excluded number of prior therapies from the model, reasoning that its optimal cutoff might change with advances in CLL therapies. IGHV did not remain significant (p=0.0592) in MVA of 5 remaining prognostic factors. Notably, del(17p) was not independently prognostic for OS. The final risk model consisted of 4 prognostic factors: B2M ≥5 mg/L, LDH elevated, HGB 〈 110 mg/L for women or 〈 120 mg/L for men, and time from initiation of last therapy 〈 24 months. Because hazard ratios for each factor were similar (range, 0.55-0.68) with overlapping confidence intervals, 1 point was assigned to each factor. The resulting score separated pts into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. Our risk model was prognostic for OS in the IBR/CIT training dataset (C-statistic 0.74 [95% CI 0.60-0.85]; log-rank p 〈 0.0001) and was validated in the IBR/CIT internal validation (C-statistic 0.79 [95% CI 0.56-0.97]; log-rank p 〈 0.0001), as well as in all 3 external validations: IDELA/CIT dataset (CS=0.71, 95% CI 0.59-0.81; log-rank p 〈 0.001); VEN/CIT dataset (CS=0.76, 95% CI 0.66-0.85; log-rank p=0.01); MCCD (CS=0.61, 95% CI 0.56-0.66; log-rank p 〈 0.001). Conclusions: We present the first validated risk model for OS in R/R CLL in the era of targeted therapies. Our model consists of 4 readily available factors (B2M ≥5 mg/L, LDH elevated, HGB 〈 110 mg/L for women or 〈 120 mg/L for men, and time from initiation of last therapy 〈 24 months), identifies 3 prognostic groups with significantly different OS, and has been validated for pts treated with all FDA approved targeted therapies: IBR, IDELA, and VEN. This identifies a well-defined cohort of pts with R/R disease with an unmet clinical need who are suitable for prospective trials targeting these pts. An exploratory analysis regarding prediction of MRD is ongoing. Figure. Figure. Disclosures Darif: Jannsen: Employment. Londhe:Jannsen: Employment. Xing:Gilead Sciences, Inc.: Employment. Mun:Genentech: Employment, Equity Ownership. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Furman:Loxo Oncology: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Other: DSMB; Acerta: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Hillmen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Novartis: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Seymour:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding. Jones:Celgene: Employment, Equity Ownership. Ferrante:Jannsen: Employment. Dreiling:Gilead: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Stark:Genentech: Employment. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Howes:Janssen: Employment. James:Pharmacyclics: Employment. Bhargava:Gilead: Employment. Zelenetz:Novartis/Sandoz: Consultancy; Abbvie: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-112989

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Nature Genetics, Springer Science and Business Media LLC, Vol. 45, No. 8 ( 2013-8), p. 868-876

Type of Medium: Online Resource

ISSN: 1061-4036 , 1546-1718

URL: Article

DOI: 10.1038/ng.2652

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2013

detail.hit.zdb_id: 1494946-5

SSG: 12

In: Cancer Medicine, Wiley, Vol. 9, No. 10 ( 2020-05), p. 3390-3399

Abstract: To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV , 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib ( 〈 420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P  = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P  = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P  = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

Type of Medium: Online Resource

ISSN: 2045-7634 , 2045-7634

URL: Issue

URL: Article

DOI: 10.1002/cam4.v9.10

DOI: 10.1002/cam4.2998

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 2659751-2